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Office on Smoking and Health (US). The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General. Atlanta (GA): Centers for Disease Control and Prevention (US); 2006.

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The Health Consequences of Involuntary Exposure to Tobacco Smoke: A Report of the Surgeon General.

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6Respiratory Effects in Children from Exposure to Secondhand Smoke

Introduction

Adverse effects of parental smoking on the respiratory health of children have been a clinical and public health concern for decades. As early as 1974, two articles published in the journal Lancet alerted readers to a possible link between parental smoking and the risk of a lower respiratory illness (LRI) among infants (Colley et al. 1974; Harlap and Davies 1974). Although adverse effects on children from exposure to secondhand tobacco smoke had already been suggested (Cameron et al. 1969; Norman-Taylor and Dickinson 1972), the association with early episodes of acute chest illnesses was of immediate and continuing interest because of the suspected long-term consequences for lung growth, chronic respiratory morbidity in childhood, and adult chronic obstructive lung disease (Samet et al. 1983).

Subsequently, many epidemiologic studies have associated parental smoking with respiratory diseases and other adverse health effects throughout childhood. The exposures covered include maternal smoking during pregnancy and afterward, paternal smoking, parental smoking generally, and smoking by others. In 1986, the evidence was sufficient for the U.S. Surgeon General to conclude that the children of parents who smoked had an increased frequency of acute respiratory illnesses and related hospital admissions during infancy (U.S. Department of Health and Human Services [USDHHS] 1986). The 1986 Surgeon General’s report also noted that in older children, there was an increased frequency of cough and phlegm and some evidence of an association with middle ear disease. The report also commented on an association between slowed lung growth in children and parental smoking. Several authoritative reviews by various agencies followed the 1986 report (U.S. Environmental Protection Agency [EPA] 1992; National Cancer Institute [NCI] 1999). Some researchers have systematically reviewed the literature and, where appropriate, carried out meta-analyses (DiFranza and Lew 1996; Uhari et al. 1996; Li et al. 1999); the most comprehensive systematic review was commissioned by the Department of Health in England (Scientific Committee on Tobacco and Health 1998). Updated versions of these reviews were then published as a series of articles in the journal Thorax ( Cook and Strachan 1997 , 1998 , 1999 ; Strachan and Cook 1997 , 1998a , b , c ; Cook et al. 1998 ). These papers later served as a foundation for the 1999 World Health Organization (WHO) consultation report on environmental tobacco smoke and child health ( WHO 1999 ). This chapter of the Surgeon General’s report presents a major update of those reviews based on literature searches carried out through March 2001. The methodology for these reviews is described later in this chapter (see “Methods Used to Review the Evidence”). Selected key references published subsequent to these reviews are included in an appendix of significant additions to the literature at the end of this report.

The section that follows focuses on the biologic basis for respiratory health effects; Chapter 2 (Toxicology of Secondhand Smoke) of this report provides further background. Separate sections review the evidence for different adverse effects of secondhand smoke exposure of children: LRIs in infancy and early childhood, middle ear disease and adenotonsillectomy, frequency of respiratory symptoms and prevalent asthma in school-age children, and cohort and case-control studies of the onset of asthma in childhood. There is also a review of the evidence for the effects of parental smoking on several physiologic measures, lung function, bronchial reactivity, and atopic sensitization. Each section concludes with a summary and an interpretation of the evidence.

Mechanisms of Health Effects from Secondhand Tobacco Smoke

This section reviews the biologic impact of secondhand smoke on the respiratory system of the child. Subsequent sections summarize the evidence for adverse health effects on infants and children and describe postulated mechanisms for these effects. Chapter 2 of this report provides additional general data on these mechanisms.

Introduction

Pregnant women who smoke expose the fetus to tobacco smoke components during a critical window of lung development, with consequences that may be persistent. In infancy and early childhood, the contributions of prenatal versus postnatal exposures to secondhand smoke are dif cult to separate because women who smoke during pregnancy almost invariably continue to smoke after their children are born. For children, exposure to secondhand smoke may lead to respiratory illnesses as a result of adverse effects on the immune system and on lung growth and development.

Lung Development and Growth

Active smoking by the mother during pregnancy has causal adverse effects on pregnancy outcomes that are well documented (USDHHS 2001, 2004). Exposure of pregnant women to secondhand tobacco smoke has also been associated with prematurity (Hanke et al. 1999), reduced birth weight (Mainous and Hueston 1994; Misra and Nguyen 1999), and small for gestational age outcomes in some studies (Dejin-Karlsson et al. 1998). However, the developmental effects on the respiratory system from maternal smoking during pregnancy extend beyond those that might be expected based on prematurity alone—the airways are particularly affected. Studies have demonstrated that lower measured airflows associated with secondhand smoke exposure are not completely explained by the reduction in somatic growth caused by maternal smoking (Young et al. 2000b). Researchers suspect that fetal growth limitations are mediated in part by the vasoconstrictive effects of nicotine, which may limit uterine blood flow and induce fetal hypoxia (Philipp et al. 1984). Fetal hypoxia, in turn, may lead to slowed fetal growth and may have direct effects on the lung, possibly affecting lung mechanics by suppressing the fetal respiratory rate. Studies have demonstrated a decrease in fetal movement for at least one hour after maternal smoking, which is consistent with fetal hypoxia (Thaler et al. 1980). Smoking during pregnancy may also negatively affect the control of respiration in the fetus (Lewis and Bosque 1995).

Researchers have proposed several mechanisms that explain the effects of maternal smoking during pregnancy on infant lung function. Animal and human studies suggest that morphologic and metabolic alterations result from in utero exposure to tobacco smoke components that cross the placental barrier (Bassi et al. 1984; Philipp et al. 1984; Collins et al. 1985; Chen et al. 1987). One study with monkeys that involved infusion of nicotine into the mother during pregnancy showed lung hypoplasia and changes in the developing alveoli (Sekhon et al. 1999). The investigators postulated that the effect was mediated by the nicotine cholinergic receptors, which showed an increased expansion and binding with nicotine administration. Further research with this model indicated altered collagen in the developing lung (Sekhon et al. 2002). Studies with this and similar models have shown a variety of effects from nicotine on the neonatal lung (Pierce and Nguyen 2002). The programming of fetal growth genes in utero may have a lifelong effect on lung development and disease susceptibility, areas of ongoing research in other diseases. There is now substantial research in progress on early life events and future disease risk that follows the general hypothesis proposed by Barker and colleagues (1996).

Exposure to secondhand smoke may also lead to structural changes in the developing lung. In a rat model, Collins and colleagues (1985) found that intra-uterine exposure of the pregnant rat to secondhand smoke was associated with pulmonary hypoplasia in the baby rats with decreased lung volumes; in this rat model, exposure reduced the number of sacules but increased their size. Brown and colleagues (1995) assessed respiratory mechanics in 53 healthy infants, and interpreted the pattern of findings to suggest that prenatal tobacco smoke exposure from smoking by the mother may lead to a reduction in airway size and changes in lung properties.

Lung maturation in utero is regulated by the endocrine environment, and the timing of secondhand smoke exposures with regard to lung development may have a lifelong impact on respiratory function. Secondhand smoke components may increase in utero stress responses that then speed lung maturation at the expense of lung growth. Several studies have demonstrated an effect on the fetal endocrine milieu secondary to secondhand smoke exposure (Divers et al. 1981; Catlin et al. 1990; Lieberman et al. 1992). Studies have also associated maternal smoking with more advanced lung maturity measured by lectin/sphingomyelin (L/S) ratios that were out of proportion to fetal size in human infants (Mainous and Hueston 1994). Cotinine levels measured in the amniotic fluid were positively correlated with L/S ratios. Studies also noted an increase in free, conjugated, and total cortisol levels, suggesting a potentially direct or indirect role for hormonal effects of secondhand smoke on the fetus (Lieberman et al. 1992). Other researchers have demonstrated higher levels of catecholamines in amniotic fluid in pregnant smokers compared with pregnant nonsmokers, further supporting an endocrine mechanism for the effect of secondhand smoke (Divers et al. 1981).

Multiple studies suggest that the effect of secondhand smoke on the development of the respiratory system begins with in utero exposure (Tager et al. 1995; Stick et al. 1996; Lodrup Carlsen et al. 1997). Stick and colleagues (1996) reported a dose-dependent effect of in utero cigarette smoke exposure in decreasing tidal flow patterns that were measured during the first three days of life (i.e., before any postnatal exposure). This effect was independent of the effect of smoking on birth weight. Hoo and colleagues (1998) evaluated respiratory function in preterm infants of mothers who did and did not smoke during pregnancy, with the goal of investigating whether the effect of prenatal tobacco smoke exposure is limited to an influence during the last weeks of gestation. The researchers observed that respiratory function was impaired in infants born preterm (an average of seven weeks early), suggesting that the adverse effect of prenatal tobacco smoke exposure is not limited to the last weeks of in utero development. The ratio of time to peak tidal expiratory flow to expiratory time (TPTEF:TE) was lower in infants exposed to secondhand smoke in utero compared with unexposed infants (mean 0.369 standard deviation [SD] 0.109 versus mean 0.426 SD 0.135, p ≤0.02). Because TPTEF:TE is associated with airway caliber, these data imply that cigarette smoke exposure in utero may affect airway development. Lower maximal forced expiratory flow at functional residual capacity (VmaxFRC) (Hanrahan et al. 1992) and diminished expiratory flows (Brown et al. 1995) in infants exposed in utero to secondhand smoke provide further support for the contention that infants of mothers who smoke during pregnancy have smaller airways. Increased airway wall thickness and increased smooth muscle, which can both lead to a decreased airway diameter, were found in infants exposed to tobacco smoke in utero who had died of sudden infant death syndrome (SIDS) (Elliot et al. 1999). In animal models of secondhand smoke exposure, fetuses of rats exposed to mainstream smoke (from active smoking) or to secondhand (sidestream) smoke had reduced lung volume, decreased elastic tissue within the parenchyma, increased density of interstitial tissue, and inadequate development of elastin and collagen (Collins et al. 1985; Vidic 1991). These animal and human data provide clear evidence for an adverse effect of in utero exposure to tobacco smoke on the developing lung. Studies also document structural changes in animal models and in exposed children who have died from SIDS. The physiologic findings suggest altered lung mechanics and reduced air flow consistent with changes in structure.

Immunologic Effects and Inflammation

The development of lung immunophenotype (i.e., the pattern of immunologic response in the lung) is considered to have a key role in determining the risk for asthma, particularly in regard to the T-helper 1 (Th1) pathway (which mediates cellular immunity) and the Th2 pathway (which mediates allergic responses). Secondhand smoke exposure may promote immunologic development along Th2 pathways, thus contributing to the intermediate phenotypes associated with asthma and with a predilection to chronic respiratory disease. Gene-environment interactions that begin in utero and persist during critical periods of development after birth represent the least understood, but potentially the most important, mechanistic route for a lasting influence of secondhand smoke. Although a meta-analysis of epidemiologic evidence suggests that parental smoking before birth (or early childhood secondhand smoke exposure) does not increase the risk for allergic sensitization, other lines of mechanistic investigation do show a variety of influences from secondhand smoke on immune and inflammatory responses (Strachan and Cook 1998b).

Secondhand smoke effects on T cells may influence gene regulation, inflammatory cell function, cytokine production, and immunoglobulin E (IgE) synthesis. These effects are particularly important to consider in regard to immune system ontogeny and for the subsequent development of allergies in childhood. Researchers have demonstrated that mainstream and sidestream smoke condensates selectively suppress the interferon gamma induction of several macrophage functions, including phagocytosis of Ig-opsonized sheep red blood cells, class II major histocompatibility complex expression, and nitric oxide synthesis, which are all representative of effects on immunity (Braun et al. 1998; Edwards et al. 1999). Alterations in antigen presentation may occur not only in the respiratory tract but also in the rest of the body where absorbed toxicants are distributed. Macrophages are potent effector cells for immune responsiveness; suppression of their ability to respond to environmental challenges could have lifelong consequences on immune function.

Immune responses may also be increased as a result of secondhand smoke exposure. Animal studies demonstrate increases in IgE, eosinophils, and Th2 cytokines (especially interleukin [IL]-4 and IL-10) with exposure to secondhand smoke. These increases may augment the potential for allergic sensitization and the development of an atopy phenotype. In mice sensitized to the ovalbumin (OVA) antigen and exposed to secondhand smoke for six hours per day, five days per week, for six weeks, researchers measured increases in total IgE, OVA-specific immunoglobulin G1, and eosinophils in the blood (Seymour et al. 1997). These measures indicate an increase in the allergic response to inhaled antigens. On the basis of the results from this mouse model, the investigators concluded that allergen sensitization with the increase in Th2 responses may contribute to the development of allergies in individuals exposed to secondhand smoke (Seymour et al. 1997). Other studies have demonstrated an increase in IL-5, granulocyte-macrophage colony-stimulating factor, and IL-2 in bronchoalveolar lavage fluid in mice exposed to OVA along with secondhand smoke. In these mouse models, interferon gamma levels decreased. Because mice exposed to OVA alone did not experience these cytokine changes, secondhand smoke appears able to induce a sensitization phenotype to a usually neutral antigen (Rumold et al. 2001). Although the animal data are stronger than the human epidemiologic data, studies in humans are supportive of an effect of tobacco smoke exposure on allergic phenotypes.

Allergies are caused by multiple interacting factors in people with underlying susceptibility. Secondhand smoke exposure both in utero and after birth may promote the development of an allergic phenotype. Antigens presented during the neonatal period in mice skew the immune development and response along a Th2 pathway (i.e., toward an allergic phenotype) (Forsthuber et al. 1996). Human fetuses, under the influence of the maternal system mediated through the placenta, may develop a Th2 preference as a response to an antigen (Michie 1998). Magnusson (1986) studied newborn children of nonallergic parents and found evidence suggesting that tobacco smoke exposure in utero may promote an allergic phenotype. A threefold increase in risk for an elevated IgE level was observed in children whose mothers smoked compared with the IgE levels in children born to nonsmoking mothers. Total cord blood IgE concentrations were substantially higher in infants of mothers who smoked (60.8 international units [IU]) compared with infants of nonsmoking mothers (9.8 IU).

Atopy may be characterized by either a positive IgE-mediated skin test or elevated specific IgE serum levels. Atopy represents a risk factor for asthma, and an increase in bronchial responsiveness has been associated with higher serum IgE levels. Human studies provide mixed evidence as to whether secondhand smoke exposures are associated with an increase in IgE-mediated responses (Weiss et al. 1985; Martinez et al. 1988; Ownby and McCullough 1988; Stankus et al. 1988). Weiss and colleagues (1985) demonstrated that maternal smoking was associated with atopy in children aged five through nine years who were evaluated by skin tests to four common allergens. Ronchetti and colleagues (1990) demonstrated an effect of exposure on IgE levels and on eosinophil counts. Eosinophil counts were at least three times higher in boys exposed to secondhand smoke compared with unexposed boys. There was a dose-response relationship between the number of cigarettes to which each boy had been exposed and the level of eosinophilia (Ronchetti et al. 1990).

Researchers showed decades ago that mainstream cigarette smoke causes airway inflammation (Niewoehner et al. 1974) and an increase in airway permeability to small and large molecules in young smokers (Simani et al. 1974; Jones et al. 1980). Given the qualitative similarities between mainstream smoke and secondhand smoke, these effects may be relevant to involuntary smoking (USDHHS 1986).

There are many specific components of secondhand smoke that may adversely affect a child’s lung. For example, a bacterial endotoxin known as lipopolysaccharide (LPS) can be detected in both mainstream and sidestream tobacco smoke. Studies have detected biologically active LPS in mainstream and sidestream smoke from regular and light experimental reference cigarettes used in the studies (mainstream: 120 ± 64 nanograms [ng] per regular cigarette, 45.3 ± 16 ng per light cigarette; sidestream: 18 ± 1.5 ng per regular cigarette, 75 ± 49 ng per light cigarette). The investigators suggested that chronic LPS exposure from cigarette smoke may contribute to the inflammatory effects of secondhand smoke (Hasday et al. 1999). Other studies show that LPS exposure may alter responses to allergen challenge (Tulić et al. 2000).

Researchers need to consider this hypothesized role of endotoxin because of the known pathologic effects of endotoxins on susceptible individuals. As a component of the cell wall of gram-negative bacteria, endotoxins are ubiquitous in the environment and may be found in high concentrations in household dust (Michel et al. 1996) and in ambient air pollution (Bonner et al. 1998). Macrophage activation may result from exposure to low concentrations of an endotoxin, leading to a cascade of inflammatory cytokines (such as IL-1, IL-6, and IL-8) and arachidonic acid metabolites, which are important in the formation of prostaglandin molecules (Bayne et al. 1986; Michie et al. 1988; Ingalls et al. 1999). Studies have documented increased levels of neutrophils in bronchoalveolar lavage fluid after a challenge with dust that contained endotoxins (Hunt et al. 1994). Reversible airflow obstruction has been associated with the inhalation of endotoxins in the air. In a cohort study of infants in Boston, Park and colleagues (2001) used a univariate model and found a significant association of wheeze in the first year of life with elevated dust endotoxin levels (relative risk [RR] = 1.29 [95 percent confidence interval (CI), 1.03–1.62]). In a multivariate model, elevated endotoxin levels in dust were associated with an increased risk for repeated wheeze illness in the first year of life (RR = 1.56 [95 percent CI, 1.03–2.38]) (Park et al. 2001). Exposure to endotoxins from secondhand smoke in utero, during infancy, and in childhood may increase airway inflammation and may interact synergistically with additional secondhand smoke exposures.

Smoking contributes generally to the particulate load in indoor air, and research documents that inhaling particles in the respirable size range contributes to pulmonary inflammation (National Research Council 2004). One consequence of particle-induced inflammation may be an intermediate phenotype with cough and wheeze in early childhood. Investigators used a guinea pig model of secondhand smoke exposure to study sensory nerve pathways for cough and airway narrowing in an effort to explain the development of cough and wheeze symptoms in children of smokers. When guinea pigs were exposed to side-stream smoke for six hours per day, five days per week, from one through six weeks of age, they demonstrated an increase in excitability of pulmonary C fibers (Mutoh et al. 1999) and rapidly adapting receptors (Bonham et al. 1996), which are believed to be primarily responsible for eliciting the re ex responses in defending the lungs against inhaled irritants and toxins (Lee and Widdicombe 2001). These studies have led to the conclusion that cough and wheeze may be produced by neural pathway stimulation and irritation.

Summary

Childhood respiratory disease covers a spectrum of diseases and underlying pathogenetic mechanisms that include infection, prenatal alterations in lung structure, inflammation, and allergic responses. There is a potential for secondhand smoke to contribute over the long term to the development of respiratory disease through altered organ maturation and immune function. Mechanisms underlying the adverse health effects of secondhand smoke vary across the phases of lung growth and development, extending from the in utero period to the completion of lung growth in late adolescence. The long-term effects of secondhand smoke is a field of ongoing research. These effects may vary among individuals because of individual genetic susceptibilities and gene-environment interactions. The discussions that follow summarize the available observational evidence concerning health effects of secondhand tobacco smoke on children, which are presumed to reflect the mechanisms reviewed above. The discussions also interpret the evidence in the context of this mechanistic understanding.

Methods Used to Review the Evidence

The search strategies and statistical methods for pooling that were used for this report were identical to those applied to the earlier reviews of this topic carried out by Strachan and Cook (1997). The authors conducted an electronic search of the EMBASE Excepta Medica and Medline databases using Medical Subject Headings (MeSH) to select published papers, letters, and review articles relating to secondhand tobacco smoke exposure in children. The EMBASE strategy was based on text word searches of titles, keywords, and related abstracts; non-English language articles were not included. The search was carried out through 2001.

Information relating to the odds ratio (OR) for the outcome of interest among children with and without smokers in the family was extracted from each study. Data regarding children exposed and unexposed to maternal smoking prenatally or postnatally were extracted separately. This review also specifically addresses the effects on children of smoking by other household members (usually the father) when the mother was not a smoker. Not every study provided information on all of these indices. The most common measures were smoking by either parent versus neither parent, and the effects of smoking by the mother versus only by the father or by neither parent. Few studies distinguished in any detail between prenatal and postnatal maternal smoking, but those that did were included in the discussion. The ORs for the effects of smoking by both parents compared with neither parent were also extracted from cross-sectional surveys of school-age children.

Because most studies have used self-reported parental smoking behaviors as the principal exposure indicator, and because the major sources of exposure in western countries are overwhelmingly maternal followed by paternal smoking (Cook et al. 1994), the terms parental, maternal, and paternal smoking are used throughout this chapter to refer to major sources of secondhand tobacco smoke exposure for children. The OR was chosen as a measure of association because it can be derived from all types of studies—case-control, cross-sectional, and cohort. In general, ORs and their 95 percent CIs were calculated from data in published tabulations using the actual numbers of participants, or numbers estimated from percentages of published column or row totals. This approach allowed for flexibility in combining categories of household tobacco smoke exposure for comparability across studies. If the number of participants was not provided, the published OR and its 95 percent CI were used. For some studies, it was necessary to derive an approximate standard error (for the log OR) based on the marginal values of the relevant multiplication table (2 × 2). In situations where ORs were given separately for different genders, a pooled OR and 95 percent CI were calculated by taking a weighted average (on the log scale) using weights inversely proportional to the variances. The papers that quoted an incidence rate ratio rather than an OR are identified in the summary tabulations.

The literature review also identified information on the extent to which the effects of parental smoking were altered by adjustment for potential confounding variables, and whether there was evidence of an exposure-response relationship with, for example, the amount smoked by either parent. Where the presented data could be standardized for age, gender, or occasionally for another confounder, the Mantel-Haenszel method was used to provide an adjusted value. Because there may be multiple published reports for a single study, only one paper from each study (usually the most recently published) was included in the quantitative meta-analyses. In some studies, however, information from other papers contributed to the assessment of potential confounding or a dose-response relationship.

Updated meta-analyses of the health effects from parental smoking were conducted specifically for this chapter. All pooled estimates were calculated using both fixed and random effects models (Egger et al. 2001). All updated analyses were carried out using Stata. For some outcomes, studies were grouped according to the timing of the secondhand smoke exposure (e.g., maternal smoking during pregnancy, parental smoking from infancy to four years of age, and parental smoking at five or more years of age).

The meta-analysis of the cross-sectional evidence relating parental smoking to spirometric indices in children updates the 1998 meta-analysis (Cook et al. 1998). Both the earlier and the more recent meta-analyses used the same effect measure: the average difference in the spirometric index between exposed and unexposed children, expressed as a percentage of the level in the unexposed group. The updated synthesis considered four different spirometric indices: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), mid-expiratory flow rate (MEFR), and flow rates at end expiration. Pooled estimates of the percentage differences were calculated using both fixed and random effects models (Egger et al. 2001).

To determine whether the exposure classification influenced the relationship between parental smoking and lung function, studies were pooled within the following exposure groups: both parents did versus did not smoke, mother did versus did not smoke, either parent versus neither parent smoked, the highest versus the lowest cotinine category, and high levels of household secondhand smoke versus none. To test for effects on the relationship between parental smoking and lung function from adjustment for variables other than age, gender, and body size, studies were pooled separately depending on adjustment for other variables. Lastly, this meta-analysis also assessed whether adjusting for socioeconomic measures, such as parental education and social class, affected the pooled results.

Lower Respiratory Illnesses in Infancy and Early Childhood

This section summarizes the evidence relating specifically to acute LRIs in the first two or three years of life and updates the previous review by Strachan and Cook (1997). Separate discussions review studies of asthma incidence, prognosis, and severity as well as studies (mostly cross-sectional) of school-age children.

In developed countries, the specific microbial etiology and determinants of some common lower respiratory tract illnesses in infancy remain a subject of uncertainty and research (Silverman 1993; Wilson 1994; Monto 2002; Klig and Chen 2003). Although many LRIs result from viral infections, there is an indication of a prenatally determined susceptibility related to lung function abnormalities that is already detectable at birth (Dezateux and Stocks 1997). As reviewed in the introduction to this chapter, lasting effects of in utero exposure to tobacco smoke from maternal smoking may increase airway resistance and the likelihood of a more severe LRI with infection. This review covers the full spectrum of LRIs, including categories considered to reflect infection and the category of wheeze, which may be a consequence of infection but may also indicate an asthma phenotype.

There is also an emerging consensus that there are several phenotypes of childhood wheeze, each with a different pattern of incidence, prognosis, and risk factors (Wilson 1994; Christie and Helms 1995). However, there is much less certainty about how these different “asthma phenotypes” should be characterized for either research or clinical purposes. Findings from the Tucson (Arizona) birth cohort study suggest physiologic and immunologic differences between the phenotypic syndromes of early childhood wheeze, the onset of asthma symptoms later in childhood, and persistent disease (Martinez et al. 1995; Stein et al. 1997). These findings have yet to be replicated in a comprehensive way in other large population samples, and few large cohort studies are in progress that provide the needed longitudinal data. The classification of phenotype in the epidemiologic studies is relevant to secondhand smoke if the association of secondhand smoke with risk varies across the phenotypes.

Relevant Studies

In the 1997 review, 75 publications were considered in detail as possibly relevant to illnesses in infancy and early childhood. Of those studies, 50 were included in the review, and 38 of those 50 were included in quantitative meta-analyses: 21 cohort studies, 10 case-control studies, 2 controlled trials, and 5 cross-sectional surveys of school-age children (Strachan and Cook 1997). The latter were included because they related parental smoking to a retrospective history of chest illness before two years of age, information that was obtained using the American Thoracic Society’s children’s questionnaire (Ferris 1978). No additional references were identified by citations in the above papers or in previous overviews.

Of 26 papers published since 1997, 17 contain quantitative information relevant to this review without duplicating the content of the other papers (Margolis et al. 1997; Nafstad et al. 1997; Baker et al. 1998; Gergen et al. 1998; Chen and Millar 1999; Dezateux et al. 1999; Gold et al. 1999; Karaman et al. 1999; Mrazek et al. 1999; Nuesslein et al. 1999; Rusconi et al. 1999; Yau et al. 1999; Diez et al. 2000; Gürkan et al. 2000b; Hjern et al. 2000; Lux et al. 2000; Young et al. 2000a). Most of these papers are community studies of wheeze illnesses: seven cohort studies, two case-control studies, and four surveys that ask about past illnesses. Only a few studies included data on the effects of smoking by only the father. The two most substantial papers analyze data from the Third National Health and Nutrition Examination Survey (NHANES III) (Gergen et al. 1998) and from a large Swedish study of hospital admissions that focused mostly on pneumonia (Hjern et al. 2000). A complement to the Swedish study examined asthma admissions, but only from two years of age and older, and was therefore not included in the quantitative synthesis (Hjern et al. 1999). That study does provide evidence relevant to effect modification by age.

Publications listed in another systematic review (Li et al. 1999) were also considered, but those studies were already included in other reviews for either LRI or asthma. Three studies from this new search were excluded: one Danish study of hospitalizations for any reason that described findings of respiratory problems, but presented no data related to secondhand smoke (Wisborg et al. 1999); a case-control study from The Gambia that considered admissions for acute LRI and implied that neither maternal nor paternal smoking was significantly associated with the outcome at p <0.05, but presented no data (Weber et al. 1999); and a cohort study of acute respiratory infections in children younger than five years of age that reported increased risks of 2.5 for pneumonia and 2.3 for other “severe disease” in children of smoking parents, but included no standard errors (Deb 1998).

Evidence Review

Community Studies of Lower Respiratory Illnesses

Combining studies from the 1997 review with subsequent publications, 34 community studies were related to parental smoking and LRIs in a community or ambulatory clinic setting (Table 6.1). There were 20 prospective cohort studies, 1 panel (short-term cohort) study, 1 cohort study carried out through record linkage, 2 controlled trials, 4 case-control studies, and 6 prevalence surveys of schoolchildren that asked parents about past illnesses. Seven studies combined all lower respiratory diagnoses (Gardner et al. 1984; Ferris et al. 1985; Pedreira et al. 1985; Wright et al. 1991; Forastiere et al. 1992; Marbury et al. 1996; Richards et al. 1996), six contributed information on bronchitis and pneumonia (Leeder et al. 1976; Fergusson and Horwood 1985; Chen et al. 1988a; Håkansson and Carlsson 1992; Gergen et al. 1998; Nuesslein et al. 1999), and two focused on illnesses diagnosed as bronchiolitis (McConnochie and Roghmann 1986b; Hayes et al. 1989). Twenty-three studies focused specifically on illnesses associated with wheeze (Fergusson and Horwood 1985; Bisgaard et al. 1987; Chen et al. 1988a; Burr et al. 1989; Lucas et al. 1990; Halken et al. 1991; Arshad et al. 1993; Tager et al. 1993; Martinez et al. 1995; Elder et al. 1996; Margolis et al. 1997; Nafstad et al. 1997; Baker et al. 1998; Gergen et al. 1998; Chen and Millar 1999; Dezateaux et al. 1999; Gold et al. 1999; Karaman et al. 1999; Mrazek et al. 1999; Rusconi et al. 1999; Yau et al. 1999; Diez et al. 2000; Lux et al. 2000; Young et al. 2000a). The studies by Baker and colleagues (1998) and Lux and colleagues (2000) both reported on the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC), and three publications contributed independent data on both bronchitis/pneumonia and wheeze illnesses (Fergusson and Horwood 1985; Chen et al. 1988a; Gergen et al. 1998).

Table 6.1

Table 6.1

Design, sample size, and recruitment criteria for studies of illness associated with parental smoking included in meta-analyses

Table 6.2 and Figures 6.16.3 summarize the results of these studies. All except one study (Nuesslein et al. 1999) found an elevated risk of LRI associated with parental smoking, including by the father only, among the studies where that exposure variable was included. The one study not finding an increased OR associated with maternal smoking reported a significant association with cotinine levels measured in meconium (Nuesslein et al. 1999). Table 6.3 presents the results of meta-analyses that pooled the results from studies of early wheeze separately from those of an unspecified LRI, bronchitis, bronchiolitis, or pneumonia. Although the effect of smoking by either parent was similar for both wheeze and LRI, maternal smoking appeared to have a somewhat greater effect than paternal smoking in studies that specifically ascertained wheeze illnesses (Table 6.3).

Table 6.2

Table 6.2

Unadjusted relative risks (odds ratios) of illness associated with parental smoking

Figure 6.1. Odds ratios for the effect of smoking by either parent on lower respiratory illnesses during infancy.

Figure 6.1

Odds ratios for the effect of smoking by either parent on lower respiratory illnesses during infancy. Note: Individual studies are denoted with the following symbols: Circles = Studies of (more...)

Figure 6.3. Odds ratios for the effect of paternal smoking on lower respiratory illnesses during infancy.

Figure 6.3

Odds ratios for the effect of paternal smoking on lower respiratory illnesses during infancy. Note: Individual studies are denoted with the following symbols: Circles = Studies of lower respiratory (more...)

Table 6.3

Table 6.3

Pooled odds ratios (ORs), 95% confidence intervals (CIs), and heterogeneity tests from meta-analyses of lower respiratory illnesses associated with parental smoking

Figure 6.2. Odds ratios for the effect of maternal smoking on lower respiratory illnesses during infancy.

Figure 6.2Odds ratios for the effect of maternal smoking on lower respiratory illnesses during infancy

Note: Individual studies are denoted with the following symbols:

Circles = Studies of lower respiratory illnesses.

Squares = Studies of wheeze illnesses.

Diamonds = Studies of upper and lower respiratory illnesses.

Open symbols = Community studies.

Closed symbols = Studies of hospitalized illnesses.

Studies of Hospitalizations for Lower Respiratory Illnesses

The literature search identified 14 studies on hospitalizations for lower respiratory complaints in early life (Harlap and Davies 1974; Sims et al. 1978; Mok and Simpson 1982; Ekwo et al. 1983; Hall et al. 1984; Taylor and Wadsworth 1987; Anderson et al. 1988; Stern et al. 1989b; Reese et al. 1992; Jin and Rossignol 1993; Victora et al. 1994; Rylander et al. 1995; Gürkan et al. 2000b; Hjern et al. 2000). Four did not distinguish between different forms of chest illnesses (Ekwo et al. 1983; Taylor and Wadsworth 1987; Stern et al. 1989b; Hjern et al. 2000), four examined bronchitis and/or pneumonia (Harlap and Davies 1974; Mok and Simpson 1982; Jin and Rossignol 1993; Victora et al. 1994), and six focused on hospital admissions for wheeze illnesses (Rylander et al. 1995) or for bronchiolitis with (Sims et al. 1978; Hall et al. 1984; Gürkan et al. 2000b) or without (Anderson et al. 1988; Reese et al. 1992) confirmation of respiratory syncytial virus (RSV) infection.

One cohort study included in the meta-analysis presented detailed findings only for hospital admissions of children from birth to five years of age, and not just for early life (Taylor and Wadsworth 1987). Data presented by age at admission suggest a similar strength of association between maternal smoking and admissions across this age span for bronchitis or pneumonia. The results for all ages were therefore included in the meta-analyses.

Only one of these studies, which was carried out in Brazil, did not find an elevated risk associated with parental smoking (Table 6.2 and Figures 6.16.3) (Victora et al. 1994). Table 6.3 summarizes the results of the meta-analyses; the pooled ORs are similar in magnitude to those derived from community studies.

One case-control study from South Africa (Kossove 1982) and one from the United Kingdom (Spencer et al. 1996) were excluded from the quantitative overview because they present only general results for a smoky atmosphere in the home and not specifically for secondhand smoke. In the South African study, the principal source of exposure was wood smoke. In the British study, infants admitted with suspected bronchiolitis were almost three times more likely to have a smoky atmosphere recorded by health visitors after visiting the home when the infant was one month of age (OR = 2.93 [95 percent CI, 1.95–4.41]).

Studies of Upper and Lower Respiratory Illnesses Combined

Five studies related parental smoking to all respiratory illnesses without distinguishing upper from lower respiratory tract diagnoses (Table 6.1) (Rantakallio 1978; Ogston et al. 1985, 1987; Woodward et al. 1990; Chen 1994). Two of these studies were based in the community (Ogston et al. 1987; Woodward et al. 1990), three related to hospitalizations for respiratory illnesses (Rantakallio 1978; Ogston et al. 1985; Chen 1994), and one (Chen 1994) synthesized the results of three earlier papers (Chen et al. 1986, 1988b; Chen 1989).

The findings of these studies are summarized in Table 6.2. Their inclusion in the overall meta-analysis changes the estimates of the effects only slightly (Table 6.3).

Effects of Retrospective Recall

For the six studies based on surveys of school-age children that relied on parental recall of LRIs during early childhood (Ekwo et al. 1983; Ferris et al. 1985; Stern et al. 1989b; Forastiere et al. 1992; Richards et al. 1996; Rusconi et al. 1999), separate meta-analyses were carried out and overall estimates that excluded these studies were calculated (Table 6.3). A separate analysis was carried out because this outcome measure is subject to a greater degree of misclassification than that of a prospective recording of illnesses. There was no clear pattern of differences for the findings of this group of studies compared with the other groups. Excluding the six studies from the overall meta-analysis had only a small effect on the pooled ORs.

Independence of Potential Confounding

About half of the cohort studies, but only a quarter of the case-control or cross-sectional studies, included estimates of the effects of parental smoking both with and without adjustment for potential confounding variables. Although different potential confounding variables were controlled for in each study, the effects of parental smoking changed little or only modestly after adjustment for the potential confounders measured in these studies (Table 6.4).

Table 6.4

Table 6.4

Effects of adjusting for potential confounders of illness associated with parental smoking

Exposure-Response Relationships

Of the 22 studies that present evidence of an exposure-response relationship within smoking families, 17 found a statistically significant relationship either with the number of smokers or with the amount smoked in the household, or specifically with the amount of maternal smoking (Table 6.2). However, a formal dose-response meta-analysis could not be carried out because of the nature of the data. In contrast, the risk when both parents smoked compared with smoking by either parent only was not substantially greater. Thirteen studies compared smoking by both parents with smoking by neither parent (Leeder et al. 1976; Ekwo et al. 1983; Fergusson and Horwood 1985; Ferris et al. 1985; Ogston et al. 1985, 1987; Taylor and Wadsworth 1987; Forastiere et al. 1992; Reese et al. 1992; Victora et al. 1994; Rylander et al. 1995; Nafstad et al. 1997; Gürkan et al. 2000b). The pooled OR is 1.67 (95 percent CI, 1.42–1.96).

Biomarkers of Exposure

Cotinine was measured as an objective marker of tobacco smoke exposure in four studies that used urine (Reese et al. 1992; Rylander et al. 1995), serum (Gürkan et al. 2000b), or meconium (Nuesslein et al. 1999). In all four studies, cotinine levels were significantly higher in the case group. These results are consistent with another small case-control study of emergency room visits for wheeze illnesses (Duff et al. 1993), which measured urinary cotinine but did not report details of parental smoking patterns.

Specific Respiratory Diagnoses

Some studies assessed the effects of parental smoking on specifically diagnosed illnesses. One study addressed tracheitis and bronchitis (Pedreira et al. 1985), another examined wheeze and pneumonia but not bronchitis or bronchiolitis (Marbury et al. 1996), and the NHANES III study found stronger effects for chronic bronchitis, asthma, and wheeze than for pneumonia (Gergen et al. 1998). One cohort study explicitly distinguished between LRIs with and without wheeze (Wright et al. 1991). The proportion of cases exposed to maternal smoking (defined as ≥20 cigarettes per day) was 14 percent in each sub-group. This finding is not entirely consistent with the pooled ORs obtained from community studies that suggest a stronger effect from maternal smoking specifically in studies of wheeze than in studies that included a broader range of chest illnesses (Table 6.3).

Seven case-control studies that focused specifically on bronchiolitis or illnesses associated with evidence of RSV infection yielded a somewhat stronger effect compared with studies of other outcomes (Sims et al. 1978; Hall et al. 1984; McConnochie and Roghmann 1986b; Anderson et al. 1988; Hayes et al. 1989; Spencer et al. 1996; Gürkan et al. 2000b). This finding, however, may reflect a positive publication bias (see “Publication Bias and Meta-Analyses” later in this chapter).

Parental Smoking at Different Ages

The early report by Colley and colleagues (1974) suggested that the effects of parental smoking on bronchitis and pneumonia incidence were most marked in the first year of life (OR = 1.96 [95 percent CI, 1.30–2.99]), and declined thereafter with the increasing age of the child to an inverse relationship in the fifth year. Results from the Dunedin (New Zealand) cohort showed a similar pattern, with a slightly greater effect in the first year than in the second year (Fergusson et al. 1981) and little evidence of an association with consultation for bronchitis or pneumonia after two years of age (Fergusson and Horwood 1985). One study reported a decline in the risk ratio for pneumonia admissions and maternal smoking during pregnancy from between 1.2 to 1.3 up to three years of age and to 1.0 at three to four years of age, but a formal test of statistical significance was not carried out for the trend (Hjern et al. 2000).

A study in Shanghai documented that the effects of smoking by persons other than the mother on hospitalizations for respiratory diseases were stronger for admissions before 6 months of age than for admissions at 7 through 18 months of age (Chen et al. 1988a). However, a significantly increased risk persisted after six months of age for children exposed to more than 10 cigarettes per day in the home (incidence ratio = 1.83 [95 percent CI, 1.03–3.24]). In the 1970 British cohort, the effects of maternal smoking on hospitalizations for wheeze illnesses, bronchitis, or pneumonia were similar at all ages up to five years (Taylor and Wadsworth 1987).

The ALSPAC is a cohort study that examined and measured both maternal smoking during pregnancy and secondhand smoke exposure during the first six months of life. The study measured the number of hours the infant was exposed as a predictor of wheeze between 6 and 18 months of age and from 18 through 30 months of age (Lux et al. 2000). There was no evidence of any reduction in the ORs across age strata. In the Isle of Wight cohort study (Arshad et al. 1993), ORs of asthmatic wheeze with maternal smoking declined from 2.5 (95 percent CI, 1.7–3.7) at one year of age to 2.2 (95 percent CI, 1.5–3.4) at two years of age and to 1.2 (95 percent CI, 0.3–2.7) at four years of age (Tariq et al. 2000).

In a Swedish study based on record linkage (Table 6.1), the authors reported a clear decrease with increasing age of the child in the OR for hospital admissions for asthma associated with maternal smoking during pregnancy (Hjern et al. 1999). The OR was 1.6 (95 percent CI, 1.4–1.8) at two years of age, but was lower and not significantly different from 1 at three to six years of age. In the NHANES III study (Gergen et al. 1998), patterns of effect by age varied with the outcome. The OR for chronic bronchitis in children under two years of age (2.2 [95 percent CI, 1.6–3.0]) was higher than the OR for children three to five years of age (1.0 [95 percent CI, 0.6–1.8]). ORs for the younger age group were also higher for wheeze (2.1 [95 percent CI, 1.5–2.9] versus 1.3 [95 percent CI, 0.8–2.0], respectively), but not for diagnosed asthma (1.7 [95 percent CI, 1.1–2.6] versus 1.7 [95 percent CI, 1.1–2.8], respectively).

Susceptible Subgroups

Infants born prematurely are one group potentially at an increased risk from parental smoking because of the still immature lungs at birth and, for some, the development of bronchopulmonary dysplasia after birth. The effects of parental smoking on early respiratory illnesses were reported in two controlled trials (Burr et al. 1989; Lucas et al. 1990), three cohort studies (Elder et al. 1996; Gold et al. 1999; Mrazek et al. 1999), and one nested case-control study (Diez et al. 2000) that recruited infants at high risk based on prematurity (Lucas et al. 1990; Elder et al. 1996), a parental history of allergy (Burr et al. 1989; Gold et al. 1999; Mrazek et al. 1999), or both (Diez et al. 2000). The ORs obtained from these studies are within the general range of the data (Table 6.2) and have therefore been included in the meta-analyses.

Only one study permits a direct comparison between high- and low-risk infants (Chen 1994). In two Chinese cohorts, an adverse effect of household smoking on hospitalizations for a respiratory disease was evident among both low birth weight (<2.5 kilograms) (OR = 6.87 [95 percent CI, 0.89–53.0]) and normal birth weight (OR = 1.36 [95 percent CI, 0.96–1.93]) infants. There was an indication of a significant effect modification by birth weight (test for interaction: p = 0.06).

Smoking by Other Household Members

The effects of smoking by other household members when the mother did not smoke are summarized in Tables 6.2 and 6.3. These findings are derived from three studies in China (Chen et al. 1988a; Jin and Rossignol 1993; Chen 1994) that included nonsmoking mothers, and 14 studies from westernized countries with data only for paternal smoking. The results are quantitatively consistent and only two of the OR estimates are less than unity. The pooled OR obtained in the meta-analysis is 1.31 (95 percent CI, 1.19–1.43). In the Chinese studies, this effect is independent of birth weight and a range of other potential confounding factors (Jin and Rossignol 1993; Chen 1994). Another study from Malaysia, which was not included in the meta-analysis because the age range of the participants was one to five years, also found an increased risk when the fathers smoked and the mothers did not report smoking (OR = 1.20 [95 percent CI, 0.86–1.67]) (Quah et al. 2000). A large national survey from Australia with an age range from birth to four years reported a significant risk of asthma associated with maternal smoking (adjusted OR = 1.52 [95 percent CI, 1.19–1.94]); there was evidence of a dose-response relationship, but no effect from paternal smoking (OR = 0.77 [95 percent CI, 0.60–0.98]) when adjusted for maternal smoking (Lister and Jorm 1998).

Prenatal Versus Postnatal Exposure

Few studies have evaluated the effects of prenatal and postnatal maternal smoking in the same sample. In western countries, too few mothers change their smoking habits in the perinatal period to offer the statistical power to reliably separate prenatal from postnatal effects. For example, in a large study based on a national British cohort, half of the children were born to mothers who had smoked during pregnancy (Taylor and Wadsworth 1987). Only 8 percent of those mothers subsequently quit, and 6 percent of the prenatal nonsmokers smoked after the child was born. The rate of having a hospitalization for LRI differed between these two groups, but not significantly (5.9 percent for those whose mothers smoked only during pregnancy versus 3.1 percent for those whose mothers smoked only after the child’s birth; OR = 1.94 [95 percent CI, 0.96–3.94]). Postnatal smoking by mothers who did not smoke during pregnancy compared with lifetime nonsmoking mothers increased the risk, but not significantly (OR = 1.36 [95 percent CI, 0.73–2.54]). The magnitude of the effect is consistent with the pooled effect in this study and in other studies when only the father smoked (Table 6.3). More recent evidence for the independent effects of prenatal and postnatal maternal smoking comes from the ALSPAC cohort study (Lux et al. 2000). The effects of maternal smoking during pregnancy were compared with those of secondhand smoke exposure by assessing the number of hours the mother smoked in the child’s presence and by including both prenatal and postnatal smoking in the same logistic regression model. For wheeze illnesses occurring between 18 and 30 months of age, independent effects were found for each smoking pattern: ORs of 1.19 (95 percent CI, 1.02–1.39) for prenatal maternal smoking and 1.17 (95 percent CI, 1.03–1.32) for postnatal secondhand smoke exposure. These effects were adjusted for the other exposure as well as for multiple other potential confounding variables.

The reported ORs in the NHANES III survey for diagnosed asthma, chronic bronchitis, wheeze, and pneumonia were similar for prenatal and postnatal maternal smoking (Gergen et al. 1998). The authors noted the difficulty of distinguishing between the two time periods and did not assess the independent effects of smoking by fathers only.

One controlled intervention study (the control arm is included in the meta-analysis) (Margolis et al. 1997) monitored the incidence of acute LRI after an intervention that was designed to reduce post-natal tobacco smoke exposure (Greenberg et al. 1994). Among 581 infants followed to six months of age, there was no difference in the incidence of episodes of cough, wheeze, or rattling in the chest between the intervention group (1.6 episodes per year of observation) and the control group (1.5 episodes per year of observation). However, the effectiveness of the intervention in reducing tobacco smoke exposure was uncertain because the mean cotinine levels did not differ between the study groups despite a reduction in reported tobacco smoke exposure of infants in the intervention group.

Publication Bias and Meta-Analyses

Publication bias might occur if studies were more likely to be published that were “positive” (i.e., with statistically significant increases in risk), or that tended to show greater effect estimates of secondhand smoke (“Use of Meta-Analysis” in Chapter 1). Figure 6.1 suggests evidence of such a bias because there are few small studies with wide confidence limits below the pooled estimate of effect, an interpretation confirmed formally by Begg’s test (Begg and Mazumdar 1994) for a nonparametric correlation between effect estimates and their standard errors (p = 0.030 after continuity correction). Egger’s test (Egger et al. 1997) provides even stronger evidence for a publication bias (p = 0.002). Maternal smoking data also showed evidence of a publication bias (Begg’s test, p = 0.221; Egger’s test, p <0.001). For smoking by fathers only, there was no evidence of heterogeneity in the ORs and no evidence of a publication bias (Begg’s test, p = 0.880; Egger’s test, p = 0.890), perhaps reflecting the fact that publication was unlikely to hinge on the presentation or significance of the data for paternal smoking.

One approach that mitigates the consequences of any publication bias is to restrict analyses to the largest studies; for this sensitivity analysis, all studies with more than 800 cases were selected. For maternal smoking, there were six studies with a pooled random effects estimate of 1.49 (95 percent CI, 1.36–1.64). For smoking by either parent, such an analysis was not possible. Of only three large studies that provided estimates, one Chinese study included only fathers who smoked (Chen et al. 1988a), and the findings of the other two studies were too divergent in their estimated ORs of 1.85 (Ferris et al. 1985) and 1.32 (Lux et al. 2000).

Three studies (Fergusson and Horwood 1985; Chen et al. 1988a; Gergen et al. 1998) appear in more than one row in Table 6.2 and were thus included as separate and independent studies in the meta-analysis. However, a sensitivity analysis confirmed that restricting the inclusion of each study to its most frequent outcome had little effect on the pooled estimates.

Evidence Synthesis

The finding of an association between parental smoking and LRI is consistent across diverse study populations and study designs, methods of case ascertainment, and diagnostic groupings (Table 6.2). The association cannot be attributed to confounding or publication bias. Only two studies found an inverse association. One small study that reported an inverse association for maternal smoking had wide confidence limits and a positive association with cotinine levels in meconium (Nuesslein et al. 1999). A study from Brazil found an inverse association with pneumonia (Victora et al. 1994). Studies in developing countries generally have tended not to find an increased risk associated with exposure of infants and children to parental smoking. This pattern may reflect the different nature of LRIs in developing countries where bacteria are key pathogens and there is a powerful effect from biomass fuel combustion (Smith et al. 2000; Black and Michaelsen 2002), and where levels of secondhand smoke exposure are possibly lower because of housing characteristics and smoking patterns.

Some variation among studies in the magnitude of OR estimates would be anticipated as patterns of smoking differed among countries and over time, and the methods of the studies were not consistent in all respects. This variation is reflected in statistically significant heterogeneity in some of the pooled analyses (Table 6.3). For this reason, the summary ORs derived under the fixed effects assumption should be interpreted with caution. The random effects method may be more appropriate in these circumstances because its wider confidence limits reflect the heterogeneity between studies. This method is, however, more susceptible to the effects of any publication bias because the random effects method gives greater weight to smaller studies. Thus, considering the largest studies only, the fixed effects estimate for maternal smoking was 1.56 and the random effects estimate was 1.72. Regardless, the pooled estimates were statistically significant and it is highly unlikely that the association emerged by chance.

The papers that have been cited were selected using keywords relevant to passive/involuntary smoking and children in the title or abstract. When cross-checked against previous reviews of involuntary smoking in children, major omissions were not identified (USDHHS 1986; USEPA 1992; DiFranza and Lew 1996; Li et al. 1999), whereas the systematic search identified relevant references not cited elsewhere. There is a possibility that the selection was biased toward studies reporting a positive association; it is more likely that statistically significant findings would be mentioned in the abstract in comparison with nonsignificant or null findings. Three of the higher ORs were derived from small case-control studies in which involuntary smoking was not the focus of the original research (Hall et al. 1984; McConnochie and Roghmann 1986b; Hayes et al. 1989), and for these three studies publication bias may have been operative. The slightly higher pooled ORs obtained by the random effects compared with the fixed effects method (Table 6.3) reflect the greater weight assigned by the random effects approach to these small studies with a relatively large OR. However, inclusion of the large Chinese studies (Chen et al. 1988a; Jin and Rossignol 1993; Chen 1994) in the meta-analysis of the effects of smoking by either parent would have had a conservative effect (i.e., a smaller pooled estimate), because few mothers smoked in these communities.

The biologic basis for the association of paternal smoking with LRI is possibly complex, and may reflect mechanisms of injury that are in play before and after birth. These mechanisms operate to make respiratory infections more severe or to possibly increase the likelihood of infection. Although viral infection is a well-characterized etiologic factor (Graham 1990), there is evidence that the severity of the illness may be determined in part by lung function abnormalities detectable from birth that result from maternal smoking during pregnancy (Dezateux and Stocks 1997). Many early childhood episodes of wheeze, including bronchiolitis, probably form part of this spectrum of viral illnesses, although other episodes may be the first evidence of more persistent childhood asthma with associated atopic manifestations (Silverman 1993; Martinez et al. 1995). The evidence does not indicate that parental smoking increases the rate of infection with respiratory pathogens. Respiratory viruses are isolated with equal frequency among infants in smoking and nonsmoking households (Gardner et al. 1984). The effect of parental smoking on the incidence of wheeze and nonwheeze illnesses appears similar, suggesting a general increase in susceptibility to clinical illness upon exposure to respiratory infections rather than to influences on mechanisms more specifically related to asthma.

The pooled results from families with nonsmoking mothers suggest that the effects of parental smoking are at least partly attributable to postnatal (i.e., environmental) exposure to tobacco smoke in the home. The somewhat stronger effects of smoking by the mother compared with other household members may be related to the role of the mother as the principal caregiver, which would explain a higher degree of postnatal exposure of the child from the mother’s smoking. However, there is also evidence pointing to altered intrauterine lung development as a specific adverse effect of maternal smoking during pregnancy (Tager et al. 1993).

The effect of parental smoking is largely independent of potential confounding variables in studies that have measured and incorporated such variables into the analyses, suggesting that residual confounding by other factors is unlikely. It thus appears that smoking by the parents, rather than characteristics of the family related to smoking, adversely affect children and cause LRIs. The evidence supports the conclusion found in other recent reviews that there is a causal relationship between parental smoking and acute LRIs (USDHHS 1986; USEPA 1992; DiFranza and Lew 1996; WHO 1997; Li et al. 1999; California EPA 2005). The findings are consistent, properly temporal in the exposure-outcome relationship, and biologically plausible. The evidence is strongest for the first two years of life. The studies that were reviewed also suggest a clear reduction in the estimated effect after two to three years of age, particularly for pneumonia and bronchitis. The failure to find statistically significant associations in some studies of older children should not be interpreted, however, as indicative of no effect of secondhand smoke exposure at older ages.

Conclusions

  1. The evidence is sufficient to infer a causal relationship between secondhand smoke exposure from parental smoking and lower respiratory illnesses in infants and children.
  2. The increased risk for lower respiratory illnesses is greatest from smoking by the mother.

Implications

Respiratory infections remain a leading cause of childhood morbidity in the United States and other developed countries and are a leading cause of childhood deaths worldwide. The effect of parental smoking, particularly maternal smoking, is of a substantial magnitude. Reducing smoking by parents, beginning with maternal smoking during pregnancy, should reduce the occurrence of LRI. Health care practitioners providing care for pregnant women, infants, and children should urge smoking cessation; parents who are unable to quit should be encouraged not to smoke in the home.

Middle Ear Disease and Adenotonsillectomy

A possible link between parental smoking and the risk of otitis media (OM) with effusion (OME) in children was first suggested in 1983 (Kraemer et al. 1983). A number of subsequent epidemiologic studies have investigated the association of secondhand tobacco smoke exposure with diseases of the ear, nose, and throat (ENT), and the evidence has been summarized in narrative reviews (USEPA 1992; Gulya 1994; Blakley and Blakley 1995; NCI 1999) and quantitative meta-analyses (DiFranza and Lew 1996; Uhari et al. 1996). Strachan and Cook (1998a) systematically reviewed the evidence relating parental smoking to acute otitis media (AOM), recurrent otitis media (ROM), OME (glue ear), and ENT surgery in children. This section updates that 1998 review following the methods described earlier. Full journal publications cited in an overview by Thornton and Lee (1999) were also considered, but abstracts and conference proceedings were not included.

Relevant Studies

In combination with the 45 reports included in the previous review, there are now 61 relating to 59 studies of possible associations between parental smoking and AOM, ROM, middle ear disease, and adenotonsillectomy in children: 19 cross-sectional surveys, 20 prospective cohort studies, 17 case-control studies, 2 uncontrolled case-series, and 1 controlled trial of surgical intervention for middle ear effusion.

Studies were grouped according to the outcome measure and whether they were included in the meta-analysis, as shown in Tables 6.5 and 6.6. Some studies contributed data to more than one outcome or age group. In total, there were 17 studies of AOM (5 were included in the meta-analysis); 28 studies of ROM with 1 study (Ståhlberg et al. 1986) that also included adenotonsillectomy (13 in the meta-analysis); 7 studies of ear infections or hearing loss in schoolchildren (all were unsuitable for the meta-analysis); and 6 studies of adenoidectomy, tonsillectomy, or sore throat (4 were included in the meta-analysis). Studies of middle ear effusion were subdivided into 2 studies of incidence (not suitable for the meta-analysis), 8 prevalence studies (reported in 9 papers) based on population surveys (6 were included in the meta-analysis), and 11 clinic-based studies of referral for glue ear surgery (all were included) and postoperative natural history (1 trial was reported in 2 papers).

Table 6.5

Table 6.5

Design, sample size, and recruitment criteria of studies of illness associated with parental smoking excluded from meta-analyses

Table 6.6

Table 6.6

Design, sample size, and recruitment criteria of studies of illness associated with parental smoking included in meta-analyses

Evidence Review

Acute Otitis Media

Episodes of acute middle ear infection are common in young children, and a variety of methods have been used to establish the diagnosis and identify the incidence of the condition. For this reason, and because few studies present quantitative information in relation to parental smoking, a quantitative meta-analysis was not included in the previous review (Strachan and Cook 1998a). However, a conclusion was reached that the limited available evidence was consistent with a weak adverse effect of parental smoking on the incidence of AOM in children, with ORs ranging from 1.0 to 1.5.

More recent publications address AOM. Some specifically excluded recurrent episodes (Gryczyńska et al. 1999; Lubianca Neto et al. 1999), but others offered no clear distinction between infrequent and frequent ear infections (Lister and Jorm 1998; Stathis et al. 1999; Tariq and Memon 1999; Rylander and Mégevand 2000). As in the previous review (Strachan and Cook 1998a), several publications offered insufficient quantitative data for a meta-analysis (Jackson and Mourino 1999; Rylander and Mégevand 2000). In one study of Swiss children attending preschool medical examinations, the OR for ear infection (not clearly defined as single or recurrent) was 1.04 (95 percent CI, 0.54–1.98) for exposures of 1 to 19 cigarettes daily at home, and 1.18 (95 percent CI, 0.58–2.39) for exposures of 20 or more cigarettes per day, with an apparent reference group of unexposed children (Rylander and Mégevand 2000). The other report only stated that parental smoking was not a significant risk factor for AOM (p = 0.52) (Jackson and Mourino 1999).

Several papers compared the effects of parental smoking on AOM and recurrent or subacute OM in the same population sample. Although the effect was stronger for AOM among Inuit children in Greenland, for example, the effect did not reach statistical significance (Table 6.6) (Homøe et al. 1999). In an Australian birth cohort, the risks associated with maternal smoking did not differ significantly across the outcomes considered: AOM, subacute OM, and a history of ear surgery (predominantly grommet insertion) (Table 6.6) (Stathis et al. 1999). In another Australian national health survey, OM (not further specified) was associated with maternal smoking (OR = 1.31 [95 percent CI, 0.95–1.80]), but the OR for health services utilization was weaker (OR = 1.04 [95 percent CI, 0.71–1.53]) (Lister and Jorm 1998).

Stathis and colleagues (1999) examined the independent effects of exposure to prenatal and postnatal maternal cigarette smoking on the three outcomes in their study at different ages. However, results were not presented for the various specific combinations of exposure, thus limiting the interpretation. In general, maternal smoking at the first prenatal visit had a greater effect compared with exposure at older ages. Smoking during the third trimester and at five years of age had few independent effects. These results need to be interpreted cautiously as there is likely to be co-linearity between early prenatal and postnatal smoking patterns.

The pooled OR for the three studies that document the effects of smoking by either parent provides less convincing evidence (OR = 0.99 [95 percent CI, 0.70–1.40]) (see “Respiratory Symptoms and Prevalent Asthma in School-Age Children” later in this chapter; see also Table 6.14).

Table 6.13

Table 6.13

Studies of phlegm and breathlessness associated with parental smoking

Recurrent Otitis Media

The epidemiologic evidence is more abundant for ROM, which is usually defined as greater than a specified number of episodes of physician-diagnosed AOM in a defined interval (Table 6.6) (Pukander et al. 1985; Ståhlberg et al. 1986; Tainio et al. 1988; Teele et al. 1989; Daigler et al. 1991; Alho et al. 1993; Stenström et al. 1993; Collet et al. 1995; Ey et al. 1995; Stenström and Ingvarsson 1997; Adair-Bischoff and Sauve 1998; Homøe et al. 1999; and Stathis et al. 1999). Studies that tested for the presence of a dose-response relationship generally found significant relationships (Table 6.7). Several studies adjusted for multiple potential confounding factors and found similar ORs before and after adjustment (Table 6.8). These results suggest that uncontrolled confounding is unlikely to be a major issue in the interpretation of the crude ORs.

Table 6.14

Table 6.14

Summary of pooled random effects (odds ratios) of respiratory symptoms associated with parental smoking

Table 6.7

Table 6.7

Unadjusted relative risks for updated meta-analysis of illness associated with parental smoking

One birth cohort study documented the relationship of parental smoking to ROM at one, three, and seven years of age (Teele et al. 1989). The size of the cohort differed for each age because of sample attrition, but the case group increased because of an accumulation of children with at least three episodes of OM. For purposes of the meta-analysis, results from the three-year follow-up were used because this age corresponds most closely to the populations in other similar studies.

Four additional studies were included in the updated meta-analysis (Stenström and Ingvarsson 1997; Adair-Bischoff and Sauve 1998; Homøe et al. 1999; Stathis et al. 1999). In the previous review, not enough papers provided results for smoking by each parent separately to derive summary measures for maternal and paternal smoking. All four additional studies contribute to a pooled estimate for maternal smoking and three contribute estimates for paternal smoking. The findings suggest that the effects are stronger for maternal smoking.

Figure 6.4 summarizes the results comparing children from smoking and nonsmoking parents. There was some evidence for heterogeneity among the nine ORs for smoking by either parent (χ2 = 16.3, degrees of freedom [df] = 8, p = 0.038). Some variation is to be expected given the different age ranges and case definitions in the studies. Under the fixed effects assumption, the pooled OR for ROM if either parent smoked is 1.32 (95 percent CI, 1.14–1.52). Using the random effects model, the pooled estimate is 1.37 (95 percent CI, 1.10–1.70). Under the fixed effects assumption, the pooled OR for ROM is 1.37 (95 percent CI, 1.19–1.59) for an association with maternal smoking and 0.90 (95 percent CI, 0.70–1.15) for an association with paternal smoking.

Figure 6.4. Odds ratios for the effect of smoking by either parent on middle ear disease in children.

Figure 6.4

Odds ratios for the effect of smoking by either parent on middle ear disease in children. ▪ AOM studies contributing to the pooled OR. ⋄ ROM studies contributing to the pooled OR.

Middle Ear Effusion: Population Surveys and Birth Cohorts

The 1997 review identified four cross-sectional or longitudinal studies of general population samples that objectively measured the presence of OME by tympanometry (Iversen et al. 1985; Zielhuis et al. 1989; Strachan 1990) or otoscopy (Etzel et al. 1992). Regardless of the diagnostic method, all studies found an increase in the prevalence of OME in children exposed to parental smoking (Table 6.7). Two additional cross-sectional studies, one from Malaysia (Saim et al. 1997) and the other from Greece (Apostolopoulos et al. 1998), were included in this meta-analysis (Figure 6.4, middle). The former study showed no association of OME with household smoking but the latter study found a significant relationship, with an OR of 1.60 (95 percent CI, 1.23–2.08) for smoking by either parent but no dose-response trend in relation to the number of cigarettes smoked daily by the parents (p = 0.85). The pooled (random effects) OR for smoking by either parent is 1.33 (95 percent CI, 1.12–1.58).

Two more recent studies followed children prospectively from birth with examinations by tympanometry and otoscopy at intervals of three months throughout the first two years of life (Paradise et al. 1997; Engel et al. 1999). These studies are not readily integrated into the earlier meta-analysis, but they do show that OME in infancy is extremely common. For instance, among 2,253 children in Pittsburgh, 48 percent had at least one episode of effusion by 6 months of age, 79 percent by 12 months of age, and 91 percent by 24 months of age (Paradise et al. 1997). In the Netherlands, parental smoking was not a risk factor for early OME (OR = 1.09 [95 percent CI, 0.84–1.41]), but a more appropriate measure for such a common outcome may be the duration of the effusion (Engel et al. 1999). The Pittsburgh study documented consistent gradients in the cumulative percentage of days with OME during the first year of life, from 18.4 percent among children not exposed to smokers in the home to 24.8 percent among children living with three or more smokers; in the second year of life the gradients ranged from 15.7 percent to 19.4 percent, respectively. Each dose-response trend was statistically significant (p <0.001), but there were no adjustments for potential confounding variables. The effects of secondhand smoke exposure during the first year of life remained significant after adjustment for area of residence, gender, socioeconomic status (SES), family size, day care, and infant feeding. The adjusted effect of having smokers in the home was not significant in the second year of life (Paradise et al. 1997).

Middle Ear Effusion: Clinic Referrals

The 1998 review considered nine studies that examined the relationship between secondhand smoke exposure and outpatient referrals or operative interventions for glue ear (Table 6.6) (Kraemer et al. 1983; Black 1985; Hinton and Buckley 1988; Hinton 1989; Barr and Coatesworth 1991; Green and Cooper 1991; Rowe-Jones and Brockbank 1992; Rasmussen 1993; Kitchens 1995). Seven of these studies that were suitable for the meta-analysis (Figure 6.4, bottom) yielded a pooled OR for smoking by either parent of 1.20 (95 percent CI, 0.90–1.60). Two additional studies from Australia (Stathis et al. 1999) and Turkey (Ilicali et al. 1999) that have also been included strengthen the evidence for an association with parental smoking, particularly by the mother (Table 6.7). The pooled OR for maternal smoking is 1.84 (95 percent CI, 1.54–2.20) compared with 1.49 (95 percent CI, 1.13–1.96) for paternal smoking.

Most of the studies in this category use the case-control design. Only one compared ORs before and after adjusting for confounders but only for age and gender (Kraemer et al. 1983). However, several case-control studies were either matched for age, gender, and SES, or the reports comment that these variables were similarly distributed among cases and controls (Table 6.8). The Australian cohort study controlled for a wider range of covariates and found a stronger association after adjustment compared with the univariate tabulations (Table 6.8) (Stathis et al. 1999). This finding weighs against residual confounding.

Middle Ear Effusion: Natural History

Studies document that OME commonly resolves spontaneously, and about one-third of the cases may remit between outpatient referrals and operative treatments. For example, in a follow-up of a case series in the United Kingdom, the rate of spontaneous resolution in children with at least one smoking parent was 31.5 percent, similar to the rate in children of non-smoking parents (31 percent) (Hinton 1989).

Insights into the long-term natural history of untreated effusions emerge from controlled trials of operative interventions for glue ear (Maw and Bawden 1993, 1994). Among 133 children followed for five years after adenoidectomy or adenotonsillectomy, the persistence of fluid at the end of the study was three times more likely if either parent smoked (OR = 3.32 [95 percent CI, 1.17–9.41]) (Maw and Bawden 1994). A similar finding emerged using a survival analysis from a trial of unilateral grommet insertion for OME (Maw and Bawden 1993). Among 66 untreated ears followed for five or more years, a spontaneous resolution of fluid was less common among children of smokers (hazard ratio = 0.44 [95 percent CI, 0.22–0.87]), implying a twofold or threefold difference in the rates of resolution between children of smokers and children of nonsmokers.

Hearing Loss

Researchers have related middle ear effusion to hearing loss (Roland et al. 1989; Roberts et al. 1995). However, only one study was found that related parental smoking to objectively confirmed hearing impairments (Lyons 1992). This study was based on a sample of 87 Irish children having routine developmental screening at 10 months of age. A persistently abnormal distraction test was five times more common in infants involuntarily exposed to cigarette smoke, and the authors calculated that 75 percent of the cases of hearing loss were attributable to secondhand smoke exposure.

Parental reports of “suspected or confirmed hearing difficulty” by five years of age were analyzed in a British birth cohort of more than 10,000 children born in 1970 (Bennett and Haggard 1998). The lifetime incidence was 8.4 percent, and was somewhat higher among children five years of age whose mothers had smoked (unadjusted OR = 1.22; no CIs were supplied). After adjustment for gender, SES, day care, and mouth breathing, the adjusted OR for maternal smoking was 1.31 (95 percent CI, 1.14–1.51).

In a birth cohort of more than 5,000 children from Brisbane (Australia), 10 percent of the children had parental reports of consultations with a physician for hearing problems by five years of age (Stathis et al. 1999). There were significant univariate associations with maternal smoking at the first prenatal clinic visit (OR = 1.35 [95 percent CI, 1.13–1.62]) and at five years of age (OR = 1.31 [95 percent CI, 1.09–1.57]).

Adenoidectomy and Tonsillectomy

The 1997 review identified four studies relating to adenoidectomy, tonsillectomy, or adenotonsillectomy without a specific reference to OME as an indicator (Table 6.6) (Said et al. 1978; Ståhlberg et al. 1986; Willatt 1986; Hinton et al. 1993). These studies documented consistent ORs relating to smoking by either parent, with a pooled OR of 2.07 (95 percent CI, 1.82–2.35). However, that pooled analysis was dominated by one large population survey of French secondary schoolchildren (Said et al. 1978). A large British cohort study was identified that showed an OR of 1.0 for parental smoking with tight 95 percent CIs (0.90–1.11) (Strachan et al. 1996) that did not overlap with those of the French study (Said et al. 1978).

More recently published data do not add substantially to this contradictory evidence, but one Polish study reported large differences in adenoid histology between children involuntarily exposed to cigarette smoke and those who were not exposed (Gryczyńska et al. 1999). Epithelial thickening, significantly fewer ciliated cells, and an increase in squamous epithelium were more common in the exposed children. These findings are consistent with chronic inflammatory changes related to cigarette smoke exposure.

Evidence Synthesis

Evidence from different study designs and for different chronic or recurrent disease outcomes related to the middle ear in young children is remarkably consistent in showing a modest elevation in risk associated with parental smoking. Although the outcome measures used are subject to misclassification, the evidence is nonetheless consistent in spite of this heterogeneity.

Subsequent publications over the last four years have not substantially affected the findings of the 1997 meta-analysis (Strachan and Cook 1998a), although quantitative summarization can now be extended to AOM. No single study addresses all of the potential methodologic concerns about selection (referral) bias, information (reporting) bias, or confounding. However, multiple studies that have considered these potential methodologic problems using objective measurements, matched designs, or multivariate analyses have found that the association of secondhand smoke exposure with middle ear disease persists with little alteration in the magnitude of the effect across studies, or within studies that controlled for potential confounding. There are multiple potential pathogenetic mechanisms related to the effects of tobacco smoke components on the upper airway (Samet 2004) (Chapter 2, Toxicology of Secondhand Smoke). A causal association between acute and chronic middle ear disease and secondhand smoke exposure is thus biologically plausible.

Conclusions

  1. The evidence is sufficient to infer a causal relationship between parental smoking and middle ear disease in children, including acute and recurrent otitis media and chronic middle ear effusion.
  2. The evidence is suggestive but not sufficient to infer a causal relationship between parental smoking and the natural history of middle ear effusion.
  3. The evidence is inadequate to infer the presence or absence of a causal relationship between parental smoking and an increase in the risk of adenoidectomy or tonsillectomy among children.

Implications

The etiology of acute and chronic middle ear disease is still a focus of investigation. Nonetheless, the finding that parental smoking causes middle ear disease offers an opportunity for the prevention of this common problem. Health care providers making diagnoses of acute and chronic middle ear disease need to communicate with parents who smoke concerning the consequences for their children.

Respiratory Symptoms and Prevalent Asthma in School-Age Children

The first reports (based on telephone surveys) documenting an adverse effect of parental smoking on the health of children were published in the late 1960s (Cameron 1967; Cameron et al. 1969). By the early 1970s, studies with more formal designs addressed respiratory symptoms (Norman-Taylor and Dickinson 1972; Colley 1974; Colley et al. 1974). Since then, many epidemiologic studies have found an association between parental smoking and respiratory symptoms and diseases throughout childhood. These outcomes were considered in the 1984 and 1986 reports of the Surgeon General (USDHHS 1984, 1986). The narrative review of the 1992 EPA risk assessment (USEPA 1992) concluded that the evidence causally relating secondhand smoke exposure at home to respiratory symptoms was very strong among preschool-age children, but less compelling in school-age children. A subsequent quantitative review did not distinguish between different types of secondhand smoke exposure and their effects at different ages (DiFranza and Lew 1996).

This section summarizes the evidence on the prevalence of respiratory symptoms and asthma in children aged 5 through 16 years, assessed from surveys carried out in schools or populations. This review includes primarily cross-sectional studies and cohorts studied at a single point in time, and updates an earlier 1997 review by Cook and Strachan (1997). A subsequent section of this chapter addresses studies on the onset of asthma and exposure to secondhand smoke. These two sets of outcome measures for asthma––prevalent and incident disease––were separated because disease prevalence reflects not only factors determining incidence, but factors affecting persistence. The studies of asthma prevalence, however, receive further consideration when assessing the evidence related to asthma onset. There are additional complexities in comparisons across studies of varied designs that arise from the different approaches used to ascertain the presence of asthma, and from the heterogeneity of the asthma phenotype by age. Additionally, wheeze, cough, phlegm, and breathlessness are common symptoms for children with asthma.

Relevant Studies

In the 1997 review, 100 articles were identified from their abstracts as possibly containing data that related the prevalence of respiratory symptoms or asthma to secondhand smoke exposure (Cook and Strachan 1997 ). If a study resulted in additional publications, those publications were used to extract the necessary data. Data from cohort studies were included only if a prevalence estimate for the cohort was available at some point. However, 39 studies were excluded for various reasons.

Out of 47 new studies identified as possibly relevant, 19 were excluded for the following reasons: 7 papers did not present any findings despite having data on symptoms and secondhand smoke (Asgari et al. 1998; Jedrychowski et al. 1998; Goren et al. 1999; Kalyoncu et al. 1999; Suárez-Varela et al. 1999; Hölscher et al. 2000; Moreau et al. 2000); 3 studies presented data that were insufficient for inclusion in a meta-analysis, although there was usually a comment about either the lack of statistical significance (Garcia-Marcos et al. 1999) or the statistical significance of the findings (Faniran et al. 1998; Peters et al. 1999); 1 study presented no separate data on children (Nriagu et al. 1999); 3 were non-English language publications (Galván Fernández et al. 1999; Vitnerova et al. 1999; Kardas-Sobantka et al. 2000); 2 publications related to studies already included (Renzoni et al. 1999; Forastiere et al. 2000); 2 studies presented data on other endpoints (Gomzi 1999; Heinrich et al. 1999); and 1 study was based on sharing a room with a smoker as the exposure indicator (Odhiambo et al. 1998).

Three additional papers presented relevant data but were not considered suitable for inclusion in a meta-analysis: a study in Taiwan (Wu et al. 1998) that merited some attention because of its size but appears to overlap with a study already included that is based on another report (Wang et al. 1999); a Danish study that focused on the underdiagnosis of asthma (Siersted et al. 1998); and a study with cohorts of secondhand smoke-exposed and unexposed children aged nine years. This study addressed postnatal secondhand smoke exposure versus in utero exposure in relation to risk for all respiratory infections, upper and lower combined (Jedrychowski and Flak 1997). In addition, a publication from 2001 that lies outside the period of the search is also included because it is based on NHANES III data and is therefore relevant to the United States (Mannino et al. 2001).

Table 6.9 summarizes the characteristics of 88 studies that were included in the quantitative overview. Some papers cover more than one study and, because they may present data on different age groups or outcomes, results may be included in several rows in subsequent tables. The rows that are included in any particular meta-analysis are clearly identified.

Table 6.8

Table 6.8

Effects of adjusting for potential confounders in each study of illness associated with parental smoking

One study that was not published in the peer-reviewed literature (Florey et al. 1983) is presented separately from the main meta-analyses because of the uniform protocol, the size of the study (approximately 22,000 children), and because only two centers appear to ever have separately published their findings on secondhand smoke in a peer-reviewed journal (Gepts et al. 1978; Melia et al. 1982). Using a standard questionnaire to parents that was based on the WHO questionnaire (Colley and Brasser 1980), the main purpose of this European study was to investigate the relationship between air pollution and respiratory health in schoolchildren; data were also collected on the number of smokers in each home.

Symptom Questionnaires

With a few exceptions, the studies reviewed here are based on data collected from questionnaires filled out by the parents. Inevitably, definitions of asthma and symptoms varied and reflected the state of development of standard questionnaires. Many early studies, particularly in the United Kingdom, used the respiratory questionnaire developed by the Medical Research Council (MRC) for adults as a starting point (MRC 1966). The purpose of this questionnaire was to study chronic respiratory symptoms, and its two most important characteristics are (1) that it did not ask about symptoms in a defined period but asked whether “a person usually coughed first thing in the morning” (cough usually in the a.m.), or whether “a child’s chest ever sounded wheezy or whistling” (wheeze ever); and (2) if the answer was yes, a second question was usually asked to elicit the severity: “Does he/she cough like this on most days or nights for as much as three months each year?” (persistent cough) or “Does he/she get this [wheeze] on most days or nights?” (persistent wheeze). In 1978, the American Thoracic Society’s Epidemiology Standardization Project published a questionnaire for children based on the adult questionnaires (Ferris 1978). The children’s questionnaire determined whether symptoms occurred only with or apart from colds, and provided information used to distinguish allergic from nonallergic asthma (Ferris 1978). More recently developed questionnaires focus on symptoms in the past 12 months and use a number of methods to assess severity (Asher et al. 1995). One particularly important questionnaire was developed for the International Study of Asthma and Allergy in Childhood (ISAAC) (Asher et al. 1995). This questionnaire has been used in many recent studies. The differences in definitions are explicitly identified in this review where possible, but for some studies a clear definition was not provided in the published report.

Many papers published since the 1997 review have been based on the multicountry ISAAC protocol (Asher et al. 1995). A parental questionnaire was used for younger children in ISAAC while the adolescents themselves completed the questionnaire or, in some locations, were administered a video questionnaire. As a result of the widespread use of the ISAAC study protocol, more of the recent publications relate to asthma (N = 17) and wheeze (N = 21) than to cough (N = 12), phlegm (N = 5), or breathlessness (none).

Evidence Review

Asthma

A total of 41 studies contained quantitative information (Table 6.10); 2 studies presented two separate sets of results (Søyseth et al. 1995; Selçuk et al. 1997). Most studies reported on “asthma ever,” which is typically a positive response to “Has this child ever had asthma?” Some studies focused on current asthma, usually defined as in the past year, while other studies specifically asked whether the diagnosis had been made by a physician. One study that reported physician consultations for wheeze is included under asthma for purposes of consistency (Strachan and Elton 1986).

Table 6.9

Table 6.9

List of secondhand smoke exposure analyses included in the meta-analysis

The OR estimates for asthma in children from families in which either parent smoked compared with children of nonsmoking parents were consistently above 1; only three ORs were below 1 (Moyes et al. 1995; Peters et al. 1996; Lam et al. 1999), but the majority of confidence limits included 1. The pooled estimate was 1.23 (95 percent CI, 1.14–1.33), but there is evidence of heterogeneity among the studies (χ230 = 78.8, p <0.001). The studies reporting the highest ORs were more likely to be early publications that had small study populations and did not adjust for potential confounders Table 6.10 and Figure 6.5. The pooled OR for the unadjusted studies is 1.26 (95 percent CI, 1.15–1.38, χ221 = 51.3, p <0.001). In contrast, the relative odds for the 18 studies that adjusted for various potential confounders are quantitatively consistent and slightly lower than those for the unadjusted studies (pooled OR = 1.22 [95 percent CI, 1.12–1.32], χ217 for heterogeneity = 39.1, p = 0.002). For the 11 studies reporting both adjusted and unadjusted ORs, the adjustment had very little effect (Table 6.10) (Somerville et al. 1988; Dekker et al. 1991; Forastiere et al. 1992; Brabin et al. 1994; Kay et al. 1995; Beckett et al. 1996; Maier et al. 1997; Selçuk et al. 1997; Agabiti et al. 1999; Chhabra et al. 1999; Ponsonby et al. 2000).

Figure 6.5. Odds ratios for the effect of smoking by either parent on asthma prevalence.

Figure 6.5

Odds ratios for the effect of smoking by either parent on asthma prevalence. *Studies that did not adjust for potential confounders. Studies that adjusted for a variety of potential (more...)

Only one of the ORs for asthma where either parent smoked was below 1; the highest ORs were from small studies that had not adjusted for potential confounders (Figure 6.5). There was clear evidence of heterogeneity of effect estimates among the unadjusted studies (pooled OR = 1.30 [95 percent CI, 1.20–1.41], χ228 for heterogeneity = 152.1, p <0.001). Among the adjusted studies, the pooled OR was only slightly lower at 1.25 (95 percent CI, 1.17–1.33), again with evidence of heterogeneity (χ224 = 88.4, p <0.001). Studies that provided both adjusted and unadjusted ORs found a similar but very small effect of adjustment (Table 6.11), except for one early Japanese study (Kasuga et al. 1979). The overall pooled OR from all of the studies, using adjusted values if available, was 1.23 (95 percent CI, 1.14–1.33) (see Table 6.14).

Table 6.10

Table 6.10

Studies of asthma prevalence associated with parental smoking

One foreign language article published in the Chinese Journal of Public Health also merits attention because of the study size: 359,000 children aged 12 through 14 years were screened, making it larger than all other cross-sectional studies combined. There is an overlap between this study in Taiwan and the data presented in another publication included in the meta-analysis (Wang et al. 1999). Disease definitions were based on an ISAAC protocol that included both a written questionnaire to parents and a video questionnaire to children. “Asthma” was based on a somewhat restrictive definition requiring the following three criteria: (1) in the parent’s questionnaire, the student’s asthma was diagnosed by a physician; (2) after watching the video, the student reported a shortness of breath similar to what was depicted in a particular scene of the video; and (3) in the past 12 months, the student reported a shortness of breath similar to what was shown in the first scene of the video and had also awakened during the night (Crane et al. 2003). “Suspected asthma” was based on a much broader definition that included cough as well as wheeze.

Although the univariate analyses of the larger study did not show an association between either the number of cigarettes per day smoked by household members or the number of household smokers and asthma risk, there was an exposure-response relationship for “suspected asthma” with the number of cigarettes smoked by household members. However, these univariate results were potentially confounded by age, gender, air pollution, and area as well as by correlates of SES. Adjusted ORs were presented only for asthma (not suspected asthma), and were controlled for gender, school grade, air pollution, burning incense, area, and physical activity. Although unadjusted ORs tended to be below 1.0 for students living in smoking households, the adjusted ORs showed an elevated risk that increased with an increasing number of household smokers. Adjusted data for the number of cigarettes smoked by household members are difficult to interpret because the results were adjusted for the number of household members who smoked. The ORs of 1.1, 1.2, and 1.3 in households with one to two, three to four, and four or more smokers, respectively, are compatible with results from the related Taiwanese paper that offers an OR of 1.08 for any exposure after adjustment. An overall effect of household smoking cannot be derived because the number of children exposed in the different groups was not reported. Two other design issues are unclear: consideration does not appear to have been made for active smoking by these 12- through 14-year-olds, although it was controlled in the analysis reported by Wang and colleagues (1999); and secondhand smoke exposure is not specified as to the source: maternal smoking, paternal smoking, and/or other household members. Data from Taiwan were not presented in the 1997 WHO publication Tobacco or Health: A Global Status Report (WHO 1997), but in mainland China it was uncommon for women to smoke. Although the ORs presented in both papers from Taiwan are thus broadly compatible with those in Table 6.14, they are more in keeping with the effects of smoking by fathers or others only, as opposed to maternal smoking or smoking by either parent.

Wheeze

Using a variety of definitions (Table 6.11), 58 studies were identified with data on wheeze that could be broadly grouped under three headings: wheeze ever, current wheeze, and persistent wheeze. Wheeze is a common but nonspecific manifestation of asthma, as it has other underlying causes, including respiratory infection.

Of the 43 studies reporting effects of smoking by either parent, the 2 studies with the highest ORs reported on wheeze that was classified as both current and persistent (Weiss et al. 1980) and on wheeze most days or nights (Lebowitz and Burrows 1976), rather than wheeze ever or current wheeze. These two studies also reported the lowest prevalence rates (Table 6.11), suggesting that the definitions probably reflected more severe wheeze. In two studies that reported on both wheeze ever and wheeze most days or nights, the ORs were greater for wheeze most days or nights (Somerville et al. 1988; Chinn and Rona 1991). More recently, one study in Hong Kong reported a slightly higher OR for current than for severe wheeze (Table 6.11) (Leung et al. 1997). Two large studies from the United Kingdom found higher odds for maternal smoking in relation to frequent attacks than for less frequent attacks (Butland et al. 1997), and for speech-limiting wheeze than for all wheeze in the past year (Table 6.11) (Burr et al. 1999). However, a smaller United Kingdom study reported stronger associations with wheeze ever than for wheeze in the past year or for speech-limiting attacks (Table 6.11) (Shamssain and Shamsian 1999). The overall pooled OR from all studies using adjusted values if available was 1.26 (Figure 6.6) (see also Table 6.14).

Figure 6.6. Odds ratios for the effect of smoking by either parent on wheeze prevalence.

Figure 6.6

Odds ratios for the effect of smoking by either parent on wheeze prevalence. *Studies that did not adjust for potential confounders. Studies that adjusted for a variety of potential (more...)

Similar to the findings for asthma, all but one of the ORs for smoking by either parent were above 1. The highest ORs were from small studies that had not adjusted for potential confounders (Figure 6.6). There was clear evidence of heterogeneity of effect among the unadjusted studies (pooled OR = 1.30 [95 percent CI, 1.20–1.41], χ228 for heterogeneity = 152.1, p <0.001). Among the adjusted studies, the pooled OR was only slightly lower (OR = 1.25 [95 percent CI, 1.17–1.33]), which again provided evidence of heterogeneity (χ224 = 88.4, p <0.001). For those studies with both adjusted and unadjusted ORs, there was a similar, very small effect of adjustment except for one early Japanese study (Table 6.11) (Kasuga et al. 1979).

For the 19 centers participating in the European Communities (EC) Study, it was possible to extract data for wheeze ever. There was no evidence of heterogeneity between centers (χ218 = 18.6, p = 0.42); the pooled OR across the 19 centers was 1.20 (95 percent CI, 1.09–1.32).

Chronic Cough

A total of 44 published studies of cough have used a variety of symptom definitions (Table 6.12). Although most of the studies were based on either the MRC or American Thoracic Society questionnaires, the largest study was based on a study-specific questionnaire (Charlton 1984). Two studies reported raised ORs for cough without wheeze (Ninan et al. 1995; Wright et al. 1996), thus emphasizing the importance of cough as a symptom. There is no suggestion that the studies reporting the lowest prevalence rates (implying a more restrictive definition) contributed the highest ORs. The pooled OR for the 26 studies with no adjustments for potential confounders was 1.45 (95 percent CI, 1.34–1.58, χ225 for heterogeneity = 84.0, p <0.001), somewhat greater than for the 16 studies that adjusted for various factors: pooled OR = 1.27 (95 percent CI, 1.21–1.33, χ215 for heterogeneity = 18.0, p = 0.26) (Figure 6.7). In four studies reporting both adjusted and unadjusted estimates, the adjustments had little impact (Bland et al. 1978; Somerville et al. 1988; Wright et al. 1996; Burr et al. 1999); the study conducted by Forastiere and colleagues (1992) was excluded because CIs were not reported for the unadjusted category. It is worth noting, however, that Wright and colleagues (1996) and Burr and colleagues (1999) adjusted for active smoking.

Table 6.11

Table 6.11

Studies of wheeze prevalence associated with parental smoking

Figure 6.7. Odds ratios for the effect of smoking by either parent on cough prevalence.

Figure 6.7

Odds ratios for the effect of smoking by either parent on cough prevalence. *Studies that did not adjust for potential confounders. Studies that adjusted for a variety of potential (more...)

Chronic Phlegm

Out of 12 studies reporting on phlegm, 4 used a definition of persistent phlegm and 3 were unclear with regard to the definition in the study report (Table 6.13); 7 out of 10 studies reported significant ORs for smoking by either parent, although all ORs were above 1 (Figure 6.8). The pooled OR for smoking by either parent was 1.35 (95 percent CI, 1.30–1.41), with no evidence of heterogeneity between studies (χ29 for heterogeneity = 4.6, p = 0.87).

Table 6.12

Table 6.12

Studies of cough prevalence associated with parental smoking

Figure 6.8. Odds ratios for the effect of smoking by either parent on phlegm and breathlessness.

Figure 6.8

Odds ratios for the effect of smoking by either parent on phlegm and breathlessness. *Adjusted and unadjusted studies.

Breathlessness

Six studies reported on shortness of breath using various definitions (Table 6.13). Only two studies reported statistically significant effects even though results were above 1 for all but one of the ORs (Figure 6.8). The pooled OR for smoking by either parent was 1.31 (95 percent CI, 1.14–1.50), with no evidence of heterogeneity (χ25 for heterogeneity = 4.6, p = 0.47).

Pooled Odds Ratios

The pooled ORs for smoking by either parent compared with smoking by neither parent are consistent across different outcomes, ranging from 1.23 for asthma to 1.35 for cough and phlegm (Table 6.14). For asthma, wheeze, and cough—for which there are sufficient studies to justify a pooled analysis—there is clear evidence of an increased risk of respiratory symptoms if only one parent smokes, regardless of whether it is only the mother or the father. Exposure to smoking only by the mother appears to have a greater effect, but a formal comparison of smoking by only the mother or father is not possible because it requires within-study estimates of standard errors for the calculation. Evidence exists of a dose-response relationship with the number of parents who smoke; the summary ORs for smoking by both parents are greater than for one parent only in all cases (Table 6.14).

Restricting Analyses to Preteens

Because a number of the cited studies cover teenagers who may be active smokers, and only some studies have included controls for active smoking, the analyses have been repeatedly restricted to those studies in Table 6.9 with no children older than 11 years of age. The results are presented in Table 6.15. Although the number of studies is markedly reduced and confidence limits are widened, the estimated ORs are similar to those in Table 6.14.

Table 6.15

Table 6.15

Summary of pooled random effects (odds ratios) associated with parental smoking restricted to studies of children aged ≤11 years

Effect of Parental Smoking at Different Ages

Modification of the effect of parental smoking as children age is quite plausible. The relationship of parental smoking to the personal exposure of their children may change as the children age, and susceptibility to secondhand smoke may also change. In addition, the constellation of symptoms, signs, and physiologic abnormalities leading to a diagnosis of asthma may vary by age. A comparison across different studies is unlikely to provide a valid assessment of the risks associated with exposure to parental smoking at different ages because of the considerable overlap of age range in many studies, different definitions of symptoms, and the need to control for active smoking in older children. However, within-study comparisons can be made if comparable information is available across age groups. For example, a large U.S. study found evidence of a reduction in the OR associated with maternal smoking and current wheeze from 1.9 among infants to 1.07 among teenagers (Table 6.11) (Stoddard and Miller 1995). Recent analyses of NHANES III data documented similar results, where ORs for current wheeze in the top versus the bottom tertile of cotinine levels declined from 4.8 (95 percent CI, 2.4–9.9) at 4 through 6 years of age to 1.5 (95 percent CI, 0.7–3.3) at 7 through 11 years of age, and to 0.9 (95 percent CI, 0.3–2.2) at 12 through 16 years of age (Mannino et al. 2001). Similarly, a large questionnaire survey in the United Kingdom found a reduction in the OR for cough from 1.60 at 8 through 10 years of age to 1.50 at 11 through 13 years of age, and to 1.12 at 14 through 19 years of age (Table 6.12) (Charlton 1984). A Korean study found that the OR for cough during a two-week period fell from 3.9 for 5-year-olds and younger to 2.6 for 6- through 11-year-olds, and to 2.0 for 12- through 14-year-olds (Park and Kim 1986). The Italian Studies on Respiratory Disorders in Childhood and the Environment reported a reduction in the odds of current asthma from 1.34 at 6 through 7 years of age to 1.17 in adolescents (Table 6.10) (Agabiti et al. 1999). In contrast, a relatively small New Zealand study found slightly higher ORs for current wheeze and cough at 13 through 14 years of age than at 6 through 7 years of age (Tables 6.11 and 6.12) (Moyes et al. 1995).

For a given level of parental smoking, the reported ORs in this review of the effects of parental smoking on LRIs in schoolchildren were somewhat lower than ORs found in infancy and early childhood. For LRIs, the pooled OR for either parent smoking was 1.57 (95 percent CI, 1.42–1.74). This pattern is consistent with previous claims of smaller effects in older children, but the contrast is less marked than has been suggested (USEPA 1992). Moreover, it is necessary to consider the level of exposure when comparing estimates of the effects, which some earlier reviews did not provide (DiFranza and Lew 1996). For the same level of maternal smoking, biomarker cotinine assessments showed that personal exposure of children to secondhand smoke declined markedly between infancy and school age (Irvine et al. 1997).

Even after entering school, salivary cotinine levels provided evidence that exposure of nonsmoking children to secondhand smoke continues to fall as children grow older; exposures also are affected by gender, geographic area, and time of year (Jarvis et al. 1992; Cook et al. 1994; Pirkle et al. 1996). This decline in cotinine levels with an increase in age is consistent with large, nationwide U.S. study data, and strongly suggests that the adverse effects of parental smoking on respiratory symptoms in their children decline with age even among schoolchildren (Stoddard and Miller 1995).

Prenatal and Postnatal Exposure

Few studies have separately analyzed the effects of past versus current exposure to secondhand smoke. An early study reported a slightly lower prevalence of cough during the day or at night in children of former smokers (14.2 percent of 634) than in the offspring of lifetime nonsmokers (15.6 percent of 320) (Colley 1974). A more recent New Zealand study found that smoking by the current primary caregiver was associated with current wheeze (OR = 1.4 [95 percent CI, 1–2.1]), whereas maternal smoking during pregnancy was not (OR = 0.9 [95 percent CI, 0.7–1.4]) (Shaw et al. 1994). In a Norwegian study, postnatal smoking by the mother was more strongly related to asthma compared with either prenatal or current smoking (Table 6.10) (Søyseth et al. 1995). A recent Scottish study reported slightly stronger effects for current maternal smoking versus prenatal maternal smoking for both wheeze (OR = 1.15 versus 1.10, respectively) and cough (1.93 versus 1.42, respectively) (Beckett et al. 1996).

Findings of an analysis of NHANES III data are relevant to the U.S. experience. In general, the effects of in utero exposure to maternal smoking did not explain the effects of current secondhand smoke exposure (Mannino et al. 2001). Specifically, being in the top tertile of current cotinine levels, after excluding any active smokers, was associated with an increased risk of both current asthma and wheeze, regardless of prenatal maternal smoking. In contrast, a small U.S. study found stronger effects of maternal smoking during pregnancy compared with current postnatal maternal smoking (Hu et al. 1997).

A study in Tasmania found that prenatal and postnatal exposure had similar health effects, with some evidence for an effect of smoking in the child’s presence (Ponsonby et al. 2000). A Swedish study reported a borderline significant effect from maternal smoking during pregnancy (1.4 [95 percent CI, 1.0–2.0]) but no effect from current parental smoking (1.0 [95 percent CI, 0.7–1.4]) (Nilsson et al. 1999). The Italian collaborative group study tended to find greater ORs in preadolescent children from pre-natal maternal smoking than from current maternal smoking, but not among adolescents (Agabiti et al. 1999). Moreover, the authors acknowledged that even in this very large study, disentangling current from past effects was problematic.

Raised ORs for respiratory symptoms in studies from China (Qian et al. 2000), Hong Kong (Lau et al. 1995; Peters et al. 1996, 1998; Leung et al. 1997; Lam et al. 1998, 1999), and Taiwan (Wang et al. 1999), where maternal smoking is uncommon, also suggest a role for postnatal secondhand smoke exposure. One Hong Kong study found that symptoms were more strongly related to smoking by grandparents than by fathers, which fit the role of grandparents as caregivers (Lam et al. 1999).

Former Parental Smoking

On balance, limited evidence suggests that there is no increase in the prevalence of respiratory symptoms among children of former smokers (Colley 1974; Shaw et al. 1994). Symptom prevalence seems to be more closely related to current maternal smoking than to prenatal maternal smoking (Søyseth et al. 1995; Beckett et al. 1996; Mannino et al. 2001), although the data are not entirely consistent (Agabiti et al. 1999). Although the data are compatible with the hypothesis that current rather than past exposure makes the predominant contribution to symptoms, the evidence is not strong. There are only a few relevant studies. One major limitation of these studies is that the exposure data were not collected prospectively and consequently, recall bias is a potential problem.

Publication Bias and Wheeze

Researchers have found evidence of publication bias, particularly for wheeze, in small published studies that have higher ORs. Some studies that reported estimated effects and confidence limits only for those exposure and outcome combinations that were statistically significant further sugest publication bias (Withers et al. 1998). However, the effect of this source of bias on the pooled ORs is small because there are so many large published studies. The similarity between the pooled OR for wheeze in published studies and in the unpublished EC Study provides further reassurance that the association is not an artifact of selective publication. Notably, however, the two EC centers whose published data have appeared in journals—Middlesbrough (Melia et al. 1982) and Ardennes(Gepts et al. 1978)—had ORs of 1.36 and 1.37, respectively, which were above the overall average for the EC Study.

Evidence Synthesis

This report has described multiple mechanisms by which secondhand smoke exposure could increase the prevalence of respiratory symptoms and asthma in childhood. Secondhand smoke exposure might increase the prevalence of respiratory symptoms and asthma through in utero effects or through in ammation and an altered lung immunophenotype from postnatal exposure. Multiple studies from diverse countries consistently show that parental smoking is positively associated with the prevalence of asthma and respiratory symptoms (including wheeze) in schoolchildren; the findings of individual studies as well as the pooled analyses show that these associations are unlikely to be attributable to chance alone. The magnitude of the effects is similar for the different outcome measures. The estimated effects, particularly for wheeze, were robust to adjustments for a wide range of potentially confounding environmental and other factors. This robustness supports the conclusion that residual confounding is unlikely to be an issue and that the associations between parental smoking and the prevalence of asthma and respiratory symptoms in schoolchildren are causal.

The case for a causal interpretation is further strengthened by the trend for the OR to increase with the number of parents who smoke (i.e., none, one, or both). In the meta-analysis, the trends with the number of smoking parents were statistically significant for asthma, wheeze, and cough, and trends were evident in most of the individual studies as well. The effect of maternal smoking is greater than that of paternal smoking, but there is nevertheless evidence for a small effect of paternal smoking. Maternal smoking is associated with higher cotinine levels in school-age children, implying that maternal smoking probably has a greater impact on the exposure of children to secondhand smoke (Cook et al. 1994). These results also imply that the increased risk for asthma and other symptoms reflects postnatal exposure, although prenatal exposure may also be a contributing factor. First, there is an effect of paternal smoking; second, risk tends to rise with the number of household smokers; third, many women who do not smoke while pregnant smoke after the birth of their children; and fourth, limited evidence shows no increase in symptoms in children of former smokers. Few studies have examined dose-response trends with the number of cigarettes smoked in the household per day or dose-response trends among exposed children alone.

The prevalence of symptoms ascertained by cross-sectional surveys is determined by both disease incidence and prognosis, and the pattern of morbidity tends to be dominated by a large number of children with mild symptoms. There are indications that secondhand smoke exposure is associated with more severe wheeze, both in studies where ORs were reported for different severity measures and in studies where ORs were highest when the prevalence of wheeze was low.

Conclusions

  1. The evidence is sufficient to infer a causal relationship between parental smoking and cough, phlegm, wheeze, and breathlessness among children of school age.
  2. The evidence is sufficient to infer a causal relationship between parental smoking and ever having asthma among children of school age.

Implications

Respiratory symptoms are common among children, even among those without asthma. Secondhand smoke exposure increases the risk for the major symptoms; these symptoms should not be dismissed as minor because they may impact the activities of the affected children. Secondhand smoke exposure is causally associated with asthma prevalence, perhaps reflecting a greater clinical severity associated with exposure. Secondhand smoke exposure, particularly at home, should be addressed by clinicians caring for any child with a respiratory complaint and particularly children with asthma.

Childhood Asthma Onset

As discussed earlier in this chapter (see “Lower Respiratory Illnesses in Infancy and Early Childhood”), parental smoking is causally associated with an increased incidence of acute LRIs, including illnesses with wheeze, in the first one or two years of a child’s life. Prevalence surveys of schoolchildren show that wheeze and diagnosed asthma are more common among children of smoking parents, with a greater elevation in risk for outcomes based on definitions of wheeze that reflect a greater severity. Evidence presented in the prior section supported conclusions that parental smoking was causally associated with respiratory symptoms and prevalent asthma; the cross-sectional evidence did not address asthma onset. This section reviews cohort and case-control studies of wheeze illnesses that provide evidence concerning the effects of parental smoking on the incidence, prognosis, and severity of childhood asthma. The design of these studies addresses the temporal relationship between exposure and disease onset. This discussion also considers case-control studies of prevalent asthma that provide findings complementary to the surveys of schoolchildren. This section represents an update of the 1998 review by Strachan and Cook (1998c).

Relevant Studies

The study findings are separated into categories by outcomes: incidence, natural history, and prevalence. Incidence data come largely from prospective cohort studies that follow groups of children without asthma and monitor the development of wheeze illnesses or a new diagnosis of asthma. Incidence studies provide evidence for factors that cause the development of asthma, including exposure to secondhand smoke. The prevalence of asthma reflects not only the incidence but also the duration of the disease or its natural history. Factors that increase the severity of asthma tend to increase prevalence, particularly if the definition of prevalent asthma incorporates elements of clinical severity.

This review includes cohort and case-control studies of asthma or wheeze that occurred after infancy and includes case series of patients with asthma that investigated parental smoking and disease severity. The literature search identified 66 relevant papers that included 11 cohort studies, 24 case-control studies, 16 uncontrolled case series, and 1 large record-linkage study. Because only a small number of cohort studies were identified, ORs relating parental smoking to the incidence and prognosis of wheeze illnesses were pooled using weights inversely proportional to their variance (the “fixed effects” assumption). The ORs from the larger number of case-control studies were pooled using a “random effects” model. A quantitative meta-analysis was not possible for studies of disease severity.

Evidence Review

Cohort Studies of Incidence

The earlier review by Strachan and Cook (1998c) identified 10 papers based on six cohort studies that documented the incidence of wheeze illnesses after the first two years of life in relation to parental smoking behaviors (Table 6.16) (Taylor et al. 1983; Fergusson and Horwood 1985; Horwood et al. 1985; Anderson et al. 1986; Neuspiel et al. 1989; Sherman et al. 1990; Martinez et al. 1992, 1995; Lewis et al. 1995; Strachan et al. 1996). Five papers addressed mainly wheeze during the preschool years (Taylor et al. 1983; Fergusson and Horwood 1985; Horwood et al. 1985; Lewis et al. 1995; Martinez et al. 1995), two studies focused on the prevalence of wheeze for the first time during the school years (Sherman et al. 1990; Strachan et al. 1996), and three papers included both early and later childhood (Anderson et al. 1986; Neuspiel et al. 1989; Martinez et al. 1992). Only one additional birth cohort study, based on very low birth weight infants, has been published since the 1998 review (Darlow et al. 2000). These studies complement the larger number of studies that address wheeze illness incidence in infancy and are reviewed in the next section. The results are summarized in Table 6.17 and Figure 6.9 and are discussed briefly in the next section.

Table 6.16

Table 6.16

Design, sample size, and recruitment criteria for studies of asthma incidence and prognosis associated with parental smoking included in this overview

Table 6.17

Table 6.17

Incidence and prognosis of asthma or wheeze in relation to parental smoking

Figure 6.9. Odds ratios for the effect of maternal smoking on asthma or wheeze incidence throughout childhood (cohort studies).

Figure 6.9

Odds ratios for the effect of maternal smoking on asthma or wheeze incidence throughout childhood (cohort studies). *Studies that included the first year of life (exact incidence period shown (more...)

Investigators in Tucson (Arizona) followed a birth cohort registered with a health maintenance organization (Martinez et al. 1995). Among 762 children followed for the first three years of life and also at six years of age, 403 had no history of wheeze, 147 had wheeze by three years of age but not at six years of age (“transient” early wheeze), 112 developed wheeze after three years of age (“late-onset” wheeze), and 100 developed wheeze before three years of age and had wheeze at six years of age (“persistent” wheeze). The incidence of wheeze before three years of age—transient and persistent combined—doubled if the mother smoked 10 or more cigarettes per day. The incidence of a later onset of wheeze was less strongly associated with maternal smoking (Table 6.17). These associations were unchanged after adjustment for gender, ethnicity, eczema, noninfective rhinitis, and maternal asthma. For a comparison with other studies of early childhood wheeze, the cumulative incidence of wheeze by six years of age is also presented in Table 6.17. Although these incidence data are presented and analyzed by maternal smoking, another publication from the same cohort study has suggested that for children in day care, smoking by the caregiver may also be of importance as a determinant of the frequency of wheeze illnesses in the third year of life (Holberg et al. 1993).

In a similar population-based birth cohort study in Christchurch, New Zealand, 1,032 children were followed at annual intervals until six years of age (Fergusson and Horwood 1985; Horwood et al. 1985). In contrast to other studies, the cumulative incidence of asthmatic symptoms that parents reported was lower if the mother smoked and higher if the father smoked. The incidence was also lower if both parents smoked versus if neither parent smoked. Analyses that used medical consultations for asthma (Horwood et al. 1985) and the frequency of asthma attacks in the first six years of life (Fergusson and Horwood 1985) showed a similar pattern.

The incidence of all forms of wheeze in the nationwide 1970 British birth cohort was ascertained retrospectively by parental recall at five years of age. The direction and strength of dose-response relationships with smoking during pregnancy (Table 6.17) and when the child was five years of age were almost identical (Lewis et al. 1995). The cumulative incidence of wheeze among children of smoking mothers was elevated and changed little after adjustment for gender, birth weight, and breastfeeding, which may have potentially confounded or modified the association (Lewis et al. 1995). There was also an increased incidence of asthma by five years of age if the mother smoked (Taylor et al. 1983). Another study based on the same birth cohort explicitly excluded wheeze in the first year of life and included information from follow-up data gathered at 5 and 10 years of age(Neuspiel et al. 1989). Maternal smoking was associated with wheeze that was labeled as bronchitis with wheeze (incidence ratio 1.44 [95 percent CI, 1.24–1.68]), but not with wheeze that was labeled as asthma (incidence ratio 0.96 [95 percent CI, 0.77–1.22]). Most of the published analyses related only to the former category, which accounted for only 38 percent of all wheeze incidents (Strachan and Cook 1998c). In the absence of maternal smoking, smoking by the father was not associated with an increased risk of bronchitis with wheeze (incidence ratio 0.99 [95 percent CI, 0.76–1.29]) and was not assessed for other forms of wheeze.

An earlier national British birth cohort of persons born in 1958 contributes information on both early and later onset of wheeze illnesses (Anderson et al. 1986; Strachan et al. 1996). As in the 1970 cohort, early wheeze illnesses were ascertained retrospectively, in this case at seven years of age, and were more common if the mother had smoked during pregnancy. This association was independent of other risk factors (Strachan et al. 1996). Among 4,583 children without a history of asthma or bronchitis with wheeze reported by parents at 7 years of age, the incidence from 7 to 16 years of age differed little according to whether the mother had smoked during pregnancy; however, there were weak, nonsignificant, and positive associations with smoking by both the mother and father at the 16-year follow-up (Table 6.17).

A smaller cohort study in Boston also found little evidence for a relationship between parental smoking and asthma incidence (Sherman et al. 1990). The study had a mean annual follow-up of nine years among 722 children with no history of asthma upon entry into the study at five to nine years of age (Table 6.17). In a second cohort study in Tucson (Arizona) that was based on a random sample of households, physician-diagnosed asthma was ascertained at one- to two-year intervals (Martinez et al. 1992). Maternal smoking was associated with an increased risk of asthma, whereas smoking by the father was not (Table 6.17). The effect of maternal smoking was stronger among less educated families, although the effect modification by educational level was not statistically significant.

A national cohort study followed 299 very low birth weight children born in New Zealand in 1986 (96 percent of all survivors) through seven years of age (Darlow et al. 2000). In this potentially vulnerable group, maternal smoking during pregnancy was associated with an increased cumulative incidence of physician-diagnosed asthma (OR = 2.0 [95 percent CI, 1.2–3.3]), but a decreased risk of requiring daily medication for asthma at seven years of age (OR = 0.6 [95 percent CI, 0.3–1.3]). This unique group was not included in the meta-analyses described below.

In quantitative meta-analyses of studies of early and later incidence of asthma and wheeze illnesses, the association with maternal smoking was significantly stronger for the first five to seven years of life (the pooled OR for the four studies = 1.31 [95 percent CI, 1.22–1.41], χ2 for heterogeneity = 8.58, p = 0.036) (Fergusson and Horwood 1985; Lewis et al. 1995; Martinez et al. 1995; Strachan et al. 1996) than for the school years (Sherman et al. 1990; Strachan et al. 1996) or throughout childhood (Neuspiel et al. 1989; Martinez et al. 1992), excluding infancy (the pooled OR for the four studies = 1.13 [95 percent CI, 1.04–1.22], χ2 for heterogeneity = 3.71, p = 0.29).

Natural History

Tables 6.16 and 6.17 summarize 11 studies that related parental smoking to the natural history of wheeze illnesses in childhood (McConnochie and Roghmann 1984; Welliver et al. 1986; Geller-Bernstein et al. 1987; Toyoshima et al. 1987; Rylander et al. 1988; Lewis et al. 1995; Martinez et al. 1995; Strachan 1995; Wennergren et al. 1997; Infante-Rivard et al. 1999; Rusconi et al. 1999). Five studies addressed the short-term prognosis of all forms of wheeze from infancy through school age (Geller-Bernstein et al. 1987; Toyoshima et al. 1987; Martinez et al. 1995; Wennergren et al. 1997; Rusconi et al. 1999). Two studies reported specifically on the prognosis of wheeze following RSV infection (Rylander et al. 1988) or bronchiolitis in infancy (McConnochie and Roghmann 1984). The results of these seven studies are all consistent with an association between parental smoking and a small but increased risk of wheeze persisting after early childhood (pooled OR = 1.49 [95 percent CI, 1.24–1.78], χ2 for heterogeneity = 28.4, p <0.001).

The short-term prognosis of bronchiolitis from a parain uenza virus infection in infancy was evaluated among 27 children after an approximate follow-up period of three years (ranging from 8 to 51 months) (Welliver et al. 1986). The mean number of subsequent wheeze episodes was significantly higher (p <0.05) in children whose parents smoked compared with children whose parents were nonsmokers (3.0 versus 1.6 episodes, respectively), but the findings cannot be expressed in the form of an OR for a direct comparison with other prognostic studies.

A contrasting pattern of effect of parental smoking on prognosis emerges from a follow-up of a longer duration in two British birth cohort studies (Lewis et al. 1995; Strachan 1995). Among children from the 1958 cohort with a history of asthma or bronchitis with wheeze by 7 years of age, maternal smoking was associated with a significantly reduced risk of these illnesses at 11 and 23 years of age (Strachan 1995), despite the tendency of children of smoking parents to become active smokers, which is strongly associated with the recurrence of symptoms (Strachan et al. 1996). In the 1970 cohort, children younger than 5 years of age with wheeze whose mothers had smoked during pregnancy were less likely to experience wheeze in the past year at 16 years of age. This inverse association was not statistically significant but changed little after adjustment for gender, maternal age, parity, birth weight, and SES (Lewis et al. 1995). The pooled OR for maternal smoking with a follow-up to 11 (1958 cohort) or 16 years of age (1970 cohort) is 0.71 (95 percent CI, 0.57–0.89, χ2 for heterogeneity = 3.58, p = 0.058).

A study in Canada that initiated a follow-up at three to four years of age found no effect of maternal smoking on the persistence of symptoms six years later (OR = 1.06 [95 percent CI, 0.67–1.67]) (Infante-Rivard et al. 1999). This result is consistent with prevalence studies that found a declining influence of parental smoking on asthmatic symptoms as the child grows older.

Prevalence Case-Control Studies

Tables 6.16 and 6.18 summarize 21 case-control studies that relate parental smoking to asthma or wheeze illnesses after the first year of life (O’Connell and Logan 1974; Palmieri et al. 1990; Daigler et al. 1991; Willers et al. 1991; Butz and Rosenstein 1992; Ehrlich et al. 1992, 1996; Infante-Rivard 1993; Clark et al. 1994; Fagbule and Ekanem 1994; Leen et al. 1994; Mumcuoglu et al. 1994; Azizi et al. 1995; Henderson et al. 1995; Lindfors et al. 1995; Rylander et al. 1995; Strachan and Carey 1995; Moussa et al. 1996; Oliveti et al. 1996; Jones et al. 1999; Chang et al. 2000). The studies are based mostly on outpatient or inpatient cases, although four ascertained more severe forms of wheeze illnesses using a population survey (Leen et al. 1994; Strachan and Carey 1995; Ehrlich et al. 1996; Moussa et al. 1996). These papers complement the results of population surveys of diagnosed asthma or symptoms of wheeze reviewed earlier in this chapter (see “Respiratory Symptoms and Prevalent Asthma in School-Age Children”) by more specifically addressing the relationship of parental smoking to the prevalence of more severe forms of asthma that require clinical care.

Table 6.18

Table 6.18

Unadjusted relative risks associated with parental smoking for asthma (meta-analysis of case-control studies)

For asthma, the results for smoking by either parent (from 15 studies) are summarized in Figure 6.10. There is evidence for borderline significant heterogeneity between studies (χ2 = 23.3, df = 14, p = 0.06), but the size of the effect does not appear to be systematically related to the age ranges studied or to the sources of cases or controls. The pooled OR for smoking by either parent, derived by random effects modeling, is 1.39 (95 percent CI, 1.19–1.64). In a comparison of the effects of maternal and paternal smoking, there is a consistent finding of an association with maternal smoking (pooled OR = 1.54 [95 percent CI, 1.31–1.81]) but not with paternal smoking (pooled OR = 0.93 [95 percent CI, 0.81–1.07]). This finding contrasts with prevalence surveys of asthma and wheeze among schoolchildren that found an effect of paternal smoking.

Figure 6.10. Odds ratios for the effect of smoking by either parent on childhood asthma or wheeze prevalence (case-control studies).

Figure 6.10

Odds ratios for the effect of smoking by either parent on childhood asthma or wheeze prevalence (case-control studies). *Derived by the random effects method.

Six studies provided findings before and after adjustment for potential confounding variables (Fagbule and Ekanem 1994; Henderson et al. 1995; Rylander et al. 1995; Strachan and Carey 1995; Ehrlich et al. 1996; Oliveti et al. 1996). Only one study from Nigeria (Fagbule and Ekanem 1994) reported a substantial reduction in the OR for smoking by either parent (from 2.12 to 1.41) after adjustment for potential confounders that included pet ownership, indoor mold, cockroaches, wood smoke, and the use of mosquito coils. The OR for parental smoking changed little (from 1.32 to 1.3) after adjustment for family history of asthma and duration of breastfeeding in Sweden (Rylander et al. 1995); in the United Kingdom the OR changed from 1.44 to 1.49 after adjustment for age, gender, SES, gas cooking, indoor mold, feather bedding, and pet ownership (Strachan and Carey 1995); in the United States the OR changed from 1.74 to 1.8 after adjustment for family history of asthma and skin-prick positivity to common aeroallergens (Henderson et al. 1995); in South Africa the OR changed from 1.97 to 1.87 after adjustment for personal and family histories of atopic disease, SES, indoor mold, and salt preference (Ehrlich et al. 1996); and in the United States the OR changed from 2.79 to 2.82 after adjustment for maternal asthma, history of bronchiolitis, and a range of obstetric and perinatal variables (Oliveti et al. 1996).

Seven studies included measurements of urinary cotinine as an objective marker of tobacco smoke exposure (Willers et al. 1991; Ehrlich et al. 1992, 1996; Clark et al. 1994; Henderson et al. 1995; Rylander et al. 1995; Chang et al. 2000). Generally, the results of questionnaire and biochemical assessments were similar, although one study (Clark et al. 1994) found a stronger association between asthma and exposure classified by cotinine levels rather than by parental smoking assessed from a questionnaire. At least one study suggested that children with asthma may differ from other children exposed to secondhand tobacco smoke in terms of a lower clearance rate for nicotine metabolites, raising the possibility of a pharma-cokinetic predisposition underlying the association between parental smoking and childhood asthma (Knight et al. 1998).

Four studies found a significant dose-response relationship of parental smoking with cotinine concentrations (Willers et al. 1991; Ehrlich et al. 1992, 1996; Chang et al. 2000), but a fifth did not (Rylander et al. 1995). Two other studies with findings for exposure-response trends based on a questionnaire assessment have inconsistent results (Palmieri et al. 1990; Strachan and Carey 1995), whereas a third, based on obstetric records, reported a strong exposure-response relationship for daily cigarette smoking by the mother during pregnancy (Oliveti et al. 1996).

Three studies compared the effects of parental smoking at different ages. In the Swedish study by Rylander and colleagues (1993, 1995), the effect of parental smoking was greater at 18 months of age than at a younger age. This pattern was the same, regardless of whether exposure was assessed by the number of smoking parents or by urinary cotinine concentrations (Rylander et al. 1995). A U.S. case-control study that measured urinary cotinine concentrations found a positive association with wheeze before two years of age, but a nonsignificant inverse relationship at older ages (Duff et al. 1993). An Italian case-control study compared the effect of parental smoking before and after six years of age (Palmieri et al. 1990). The ORs for smoking by either parent were, respectively, 1.13 (95 percent CI, 0.71–1.80) and 0.83 (95 percent CI, 0.48–1.44).

In this context, it is relevant to note that a large record-linkage study of hospital admissions for asthma in Sweden (see “Respiratory Symptoms and Prevalent Asthma in School-Age Children” earlier in this chapter) found a significant effect of maternal smoking only on hospital admissions for children under three years of age (Hjern et al. 1999).

Atopic and Nonatopic Wheeze

In the 1958 British birth cohort, the increased incidence of bronchitis with wheeze or asthma by 16 years of age among children whose mothers had smoked during pregnancy occurred only among the 3,815 participants with no history of hay fever, allergic rhinitis, or eczema (cumulative incidence was 24.5 percent versus 18.9 percent among those with a history, OR = 1.39 [95 percent CI, 1.18–1.63]) (Strachan et al. 1996). Among the 1,794 participants reporting hay fever, allergic rhinitis, or eczema at one or more follow-up visits, maternal smoking had little effect on disease incidence (cumulative incidence was 32.2 percent among those whose mothers had smoked during pregnancy versus 33.5 percent among those whose mothers had not smoked during pregnancy, OR = 0.95 [95 percent CI, 0.76–1.18]). The difference in the effect of maternal smoking during pregnancy by the presence or absence of hay fever, allergic rhinitis, or eczema was statistically significant (p <0.01).

In the Italian case-control study, cases (but not controls) were tested by skin prick with six locally relevant aeroallergens (Palmieri et al. 1990). Fewer prick-positive cases were exposed to any parental smoking than were prick-negative cases (77 percent versus 82 percent, respectively, OR = 0.72 [95 percent CI, 0.37–1.41]). The association of exposure with a positive skin-prick result was more marked and statistically significant at the 5 percent level with exposure to more than 20 cigarettes a day (44 percent for those exposed to ≤20 cigarettes per day versus 60 percent for those exposed to >20 cigarettes per day, OR = 0.54 [95 percent CI, 0.31–0.92]). Among 70 children with asthma aged younger than six years in a British out-patient series, maternal smoking was less common if the serum IgE was elevated (>1 SD above the population mean): 54 percent versus 69 percent among those who did not have an elevated serum Ig (OR = 0.54 [95 percent CI, 0.21–1.45]) (Kershaw 1987). A cross-sectional survey of Canadian children also identified a stronger association between parental smoking and recent asthma among children with no reported history of an allergy (OR for current smoking by either parent = 2.93 [95 percent CI, 0.83–10.3]) than among children with an allergy (OR = 0.73 [95 percent CI, 0.37–1.46]) (Chen et al. 1996). Although these differences are nonsignificant, they are consistent with the 1958 British birth cohort study results and thus suggest a stronger association between parental smoking and nonatopic “wheezy bronchitis” than with “allergic asthma.”

A recent cross-sectional study of six- to seven-year-old children in northern Sweden presented results separately for atopic and nonatopic asthma defined by the presence or absence of positive skin-prick tests (Ronmark et al. 1999). Maternal smoking was significantly associated with nonatopic asthma (OR = 1.67 [95 percent CI, 1.04–2.68]) but not with atopic asthma (OR = 1.17 [95 percent CI, 0.68–2.01]). Because the study data were not fully displayed, effect modification by atopy cannot be formally evaluated for statistical significance.

A contrasting pattern was found in a study of allergy clinic patients aged 1 through 17 years in Vancouver (Canada) (Murray and Morrison 1990). Among 224 patients with atopic dermatitis, maternal smoking was associated with an increased risk of diagnosed asthma (OR = 3.42 [95 percent CI, 1.60–7.30]), whereas among 396 patients without atopic dermatitis there was no association (OR = 0.93 [95 percent CI, 0.57–1.51]). This interaction is statistically significant at the 1 percent level, but the findings are difficult to interpret biologically without the consideration of possible referral biases in this clinic-based study.

Severity

The severity of an episodic disease such as asthma has several dimensions: frequency of wheeze episodes, persistence of symptoms between “attacks,” occurrence of clinically severe or life-threatening bronchospasm, the need for preventive and/or rescue medications, health services utilization, and interference with daily activities. Seven population surveys (Gortmaker et al. 1982; Weitzman et al. 1990a,b; Strachan and Carey 1995; Ehrlich et al. 1996; Chew et al. 1999; Schwartz et al. 2000), 1 case-control study (Henderson et al. 1995), 11 uncontrolled case series (Aderele 1982; Evans et al. 1987; Murray and Morrison 1989, 1993; Chilmonczyk et al. 1993; LeSon and Gershwin 1995; Macarthur et al. 1996; Minkovitz et al. 1999; Wafula et al. 1999; Gürkan et al. 2000a; Sandberg et al. 2000), and 1 record-linkage study (Hjern et al. 1999) present data on asthma severity in relation to parental smoking (Table 6.19). Various dimensions of severity were used and some studies combined a number of indices into a composite “severity score” (Aderele 1982; Murray and Morrison 1989, 1993).

Table 6.19

Table 6.19

Design, sample size, and severity index for studies of asthma severity associated with parental smoking included in this overview

Because each study employed different approaches, a formal quantitative meta-analysis was not carried out, but Table 6.20 presents a qualitative review. These studies suggest greater disease severity in children exposed to smoking at home, a pattern that is more consistently found among persons with asthma who are hospital outpatients or inpatients than among children with asthma identified through population surveys (Table 6.20).

Table 6.20

Table 6.20

Summary of studies on asthma severity associated with parental smoking

Several studies adjusted for potential confounding variables, and it is possible that some of the associations of parental smoking with health service utilization, in particular, may reflect a common association with a lower SES and correlates of SES that affect utilization. On the other hand, the striking association of secondhand tobacco smoke exposure with near-fatal asthma, evaluated retrospectively in a tertiary medical care center in California, was stronger than a range of psychosocial variables, which suggests that the association cannot be entirely explained by SES confounding (LeSon and Gershwin 1995). However, a mutually adjusted analysis was not possible as only 2 of the 13 patients who required intubation came from nonsmoking households.

Effects of Reducing Tobacco Smoke Exposure

Information on secondhand smoke exposure and asthma severity can also be found in studies that track the consequences of exposure reduction. According to the early case-control study by O’Connell and Logan (1974), 67 percent of the 265 children who were exposed to parental smoking considered that it had aggravated their symptoms. In addition, tobacco smoke exposure was considered a “significant factor” for symptoms in 10 percent (16/158) of children if one parent smoked and in 20 percent (21/107) if both parents smoked. These 37 children were included in an empirical study of antismoking advice that included a follow-up 6 to 24 months later of 35 of the children. Symptoms improved in 90 percent (18/20) of the children whose parents had stopped smoking, and in 27 percent (4/15) of the children who remained involuntarily exposed to tobacco smoke. These results suggest a benefit from reducing exposure, but interpretation is limited by the nonrandomized nature of the intervention.

A composite score was used to grade severity among 415 children aged 1 through 17 years diagnosed with asthma who attended an allergy clinic in Vancouver (Canada) from 1983 to 1986 (Murray and Morrison 1989). The severity score was significantly higher among children of smoking mothers (p <0.01), but when the analysis was repeated for an additional 387 children attending the same clinic from 1986 to 1990, the relationship between maternal smoking and the asthma severity score was reversed, reflecting a highly significant (p <0.001) decline in severity among children of smoking mothers, and little change in severity for children whose mothers did not smoke (Murray and Morrison 1993). The authors attributed this change to an alteration in parental smoking behaviors following advice from clinicians to avoid smoking in the home or in the presence of the child. However, this interpretation was based on anecdotal reports, and no objective data were presented to confirm the postulated reduction in the personal exposure of the children.

Evidence Synthesis

The results summarized in this discussion and in previous sections present a complex picture of the associations of parental smoking with asthma incidence, prognosis, prevalence, and severity. The rates of incidence and recurrence of wheeze illnesses in early life are greater if there is smoking in the home, particularly by the mother, whereas the incidence of asthma during the school-age years is less strongly affected by parental smoking. A similar age-related decline in the strength of the effect of secondhand smoke exposure is evident in cross-sectional studies. These findings may simply reflect the diminishing level of secondhand tobacco smoke exposure from household sources as children age (Irvine et al. 1997; Chang et al. 2000). Alternatively or additionally, parental smoking may have differential effects on the incidence of various forms of wheeze illnesses; there may be a stronger effect on the viral infection associated with wheeze that is common in early childhood, and a weaker effect on the atopic wheeze that occurs often as a later onset component of asthma (Wilson 1989). Five studies comparing the effect of smoking on wheeze in atopic and nonatopic children lend support to the latter hypothesis (Kershaw 1987; Palmieri et al. 1990; Chen et al. 1996; Strachan et al. 1996; Ronmark et al. 1999), but a sixth does not (Murray and Morrison 1990).

The earlier section on LRIs in infancy presented evidence of an increased risk from postnatal exposure to smoking by the father in households where the mother did not smoke, but there was insufficient evidence to distinguish the separate effects of prenatal and postnatal smoking by the mother. Several of the cohort studies reviewed here have reported findings in relation to maternal smoking during pregnancy. These data are limited, and the potential role of prenatal exposure as an independent cause of asthma is still unclear. The published data are insufficient to assess the independent effect of nonmaternal smoking on the incidence or natural history of childhood asthma after the first few years of life. Most cohort studies show a weak association of asthma incidence with paternal smoking. In case-control studies, maternal smoking has the dominant effect, with little effect from smoking by the father.

Although wheeze in infancy is more likely to recur if both parents smoke, at least maternal smoking alone is associated with seemingly little long-term risk (Table 6.17). This indication could also reflect a stronger association of parental smoking with nonatopic wheeze (“wheezy bronchitis” than with “allergic asthma”), which is associated with a better prognosis. On the other hand, atopic children tend to have more severe and more frequent or persistent wheeze, and case-control studies of (“clinic”) children with more severe asthma show a positive association with maternal smoking that again appears to be of greater importance. Indeed, the pooled OR for smoking by either parent from these case-control studies (1.39) is somewhat greater than the corresponding pooled ORs from cross-sectional surveys of wheeze (1.27) and asthma (1.22) among schoolchildren. Furthermore, most studies have found a greater severity of disease among children with asthma if the parents smoke (Table 6.20), and prevalence surveys among schoolchildren suggest a stronger association with more restrictive (presumably more severe) definitions of wheeze than with any recent wheeze.

These findings by age and phenotype are complex to interpret: studies of incidence and prognosis suggest an association of parental smoking primarily with early, nonatopic wheeze that tends to run a mild and transient course, whereas studies of prevalence and severity suggest that secondhand tobacco smoke exposure increases the risk of more severe symptoms and more outpatient clinic visits or emergency hospital admissions. One explanation for this pattern would be to consider secondhand tobacco smoke as a cofactor operating with intercurrent infections as a trigger of wheeze attacks, rather than as a factor initiating or inducing persistent asthma. This distinction between induction (initiation) and exacerbation (provocation) also emerges when considering the role of outdoor air pollution as a cause of asthma (Department of Health Committee on the Medical Effects of Air Pollutants 1995). There is also strong familial aggregation for childhood asthma that certainly has genetic determinants, although research on the genetics of asthma is still inconclusive.

The incidence of both wheeze and nonwheeze LRIs in infancy increases to a similar extent if both parents smoke, and the increase reflects, at least in part, postnatal secondhand (environmental) tobacco smoke exposure. It is likely that the clinical severity of viral respiratory infections in older children is also exacerbated by secondhand smoke exposure, which leads to an increased risk of respiratory symptoms in general, including wheeze. Among children at low risk for wheeze, secondhand smoke exposure at the time of an intercurrent infection may be sufficient to cause occasional episodes of asthmatic symptoms and thus increase the risk of a mild, often transient wheeze tendency that the child outgrows as the airways become larger or less reactive with increasing age. In a previous section of this chapter, the conclusion was reached that secondhand smoke exposure from parental smoking causes LRIs in infants and children. The wheezing that accompanies many of these LRIs may be clinically classified as asthma, although the cohort study findings suggest that this phenotype is not generally persistent as the child ages.

Some previous reviews have concluded that exposure to secondhand smoke is causally associated with an increase in the incidence of childhood asthma (USEPA 1992; Halken et al. 1995). This association has been attributed to chronic (but possibly reversible) effects of parental smoking on bronchial hyperreactivity rather than to the acute effects of cigarette smoke on airway caliber (USEPA 1992). The most relevant evidence for secondhand smoke exposure and onset of asthma comes from studies of older children at an age when there is reasonable diagnostic certainty. This evidence comes from only a small number of studies and their statistical power is limited, particularly within specific age strata. In addition, all studies are inherently limited by the difficulty of classifying the outcome, and there may be variations in the phenotypes that were considered across the studies. Within these constraints, the evidence indicating an association of secondhand smoke exposure from parental smoking with asthma incidence is inconsistent. The evidence for asthma prevalence, by contrast, was sufficient to support an inference of causality.

Conclusions

  1. The evidence is sufficient to infer a causal relationship between secondhand smoke exposure from parental smoking and the onset of wheeze illnesses in early childhood.
  2. The evidence is suggestive but not sufficient to infer a causal relationship between secondhand smoke exposure from parental smoking and the onset of childhood asthma.

Implications

The etiology of childhood asthma includes the interplay of genetic and environmental factors. The asthma phenotype likely comprises several distinct entities. The evidence is clear in showing that secondhand smoke exposure causes wheeze illnesses in early life and makes asthma more severe clinically. This evidence provides a strong basis for limiting exposure of infants and children to secondhand smoke, even though a causal link with asthma onset is not yet established for asthma incidence.

Atopy

The hypothesis that secondhand tobacco smoke exposure might increase allergic sensitization was first proposed more than 20 years ago (Kjellman 1981). However, the role of secondhand smoke exposure (specifically from maternal smoking) in allergic sensitization remains uncertain despite many investigations since that time. Some studies have documented an association between maternal smoking during pregnancy and elevated cord blood total IgE, as well as an elevated risk for the development of allergic disease (Magnusson 1986; Bergmann et al. 1995). Other studies, however, have not replicated these findings (Halonen et al. 1991; Oryszczyn et al. 1991; Ownby et al. 1991). Many studies have investigated the relationships of secondhand smoke exposure from parental smoking with cord blood IgE concentrations, IgE levels later in childhood, skin-test reactivity, and allergic manifestations such as rhinitis (Strachan and Cook 1998c). The comprehensive, systematic review reported by Strachan and Cook (1998c) of the effects of secondhand smoke exposure from parental smoking covered IgE levels, skin-prick test reactivity, and allergic rhinitis and eczema. The review included 9 studies of IgE levels in neonates, 8 studies of IgE levels in older children, 12 studies of skin-prick tests, and 10 studies of allergic symptoms (Strachan and Cook 1998c). The quantitative summary did not show a significant association of maternal smoking with total serum IgE, allergic rhinitis, or eczema. The meta-analysis for skin-prick test positivity and smoking during infancy and pregnancy yielded a pooled OR estimate of 0.87 (95 percent CI, 0.62–1.24), suggesting no effect of secondhand smoke on skin-prick positivity during these stages of development. The summary estimate supported a conclusion that maternal smoking before birth or parental smoking during infancy is unlikely to increase the risk of allergic sensitization.

This conclusion remains consistent with results from studies conducted since this systematic review, which also found no increase in risk for allergic sensitization from secondhand smoke exposure. The discussion that follows reviews some of the key studies published since 1997 (Table 6.21).

Table 6.21

Table 6.21

Atopy studies of markers for exposure to secondhand smoke

Immunoglobulin E

Evidence for the level of cord blood IgE as a predictor of IgE-mediated disease is inconsistent. Some studies suggest that cord blood IgE predicts the development of allergic disease (Michel et al. 1980; Magnusson 1988), but others do not support that hypothesis (Halonen et al. 1991; Ruiz et al. 1991; Hansen et al. 1992). If maternal smoking during pregnancy influences immune system development and gene expression in the fetus, then the cord blood IgE concentration may be a biomarker for the effects of smoking. However, expression of genes primed in the fetal environment may not be manifest until later in life, so the complete effect of in utero tobacco smoke exposure on allergic phenotypes may not be apparent until adulthood.

A study by Kaan and colleagues (2000) examined cord blood IgE and cotinine levels in a cohort of 62 infants. The infants were part of a randomized trial of primary intervention for the prevention of asthma and allergic disease. As expected, infants of mothers who smoked at the time of study recruitment had significantly higher cotinine levels when compared with unexposed children and with children exposed to secondhand smoke from smoking by the father or other household adults. Although cord blood IgE was a significant predictor of food allergy at 12 months of age, cord blood IgE and cotinine levels were not correlated. The investigators concluded that the cord blood IgE level is not influenced by maternal smoking (Kaan et al. 2000). It should be noted that cord blood IgE values have the weakest relationship with allergy and these data should be considered separate from measures of whole blood IgE obtained at postnatal and childhood time points.

In a cohort study of 342 children followed from birth to early childhood, prenatal and postnatal tobacco smoke exposure was investigated to assess whether secondhand smoke exposure has a role in the development of allergic sensitization to food allergens during infancy and childhood (Kulig et al. 1999). The researchers collected cord blood and used a questionnaire to evaluate secondhand smoke exposure. At three years of age, children with a history of prenatal and postnatal tobacco smoke exposure had a higher risk of food allergen sensitization than children with no exposure (OR = 2.3 [95 percent CI, 1.1–4.6]). There was no association between secondhand smoke exposure and quantitative measures of cord blood IgE (p = 0.58) (Kulig et al. 1999). Another birth cohort study of 1,218 infants measured cord blood IgE levels in 1,064 infants (Tariq et al. 2000). Maternal smoking was evaluated at birth and again when the children were one, two, and four years of age; 20.5 percent of the mothers reported smoking during pregnancy and 25.2 percent reported smoking after childbirth. Maternal smoking during pregnancy was not associated with cord blood IgE levels at birth (Tariq et al. 2000).

Allergic Sensitization During Childhood

Other studies published since 1997 have investigated childhood IgE levels and exposure to secondhand tobacco smoke. Lindfors and colleagues (1999) investigated 189 children with asthma aged one to four years. The researchers explored the association between exposures to dog and cat allergens and the risk for allergic sensitization, and assessed whether the risk of allergen sensitization was modified by secondhand smoke exposure (Lindfors et al. 1999). In this study, questionnaires were completed regarding exposures to dogs, cats, home dampness as indicated by window pane condensation, and secondhand smoke, which was evaluated from questions about parental smoking in the home during the child’s first two years of life; house dust was also analyzed. Exposure to secondhand tobacco smoke increased the risk for allergic sensitization to cats (Radioallergosorbent Test [RAST] e1 cat ≥ 0.35 kilounit per liter (kU/L), OR = 2.2 [95 percent CI, 0.9–4.9]; RAST e1 cat ≥ 0.70 kU/L, OR = 2.1 [95 percent CI, 0.7–6.5]). Exposure to secondhand smoke also increased the risk for sensitization to dogs (RAST e5 dog ≥ 0.35 kU/L, OR = 2.0 [95 percent CI, 0.9–4.5]). With joint exposure to cats, secondhand smoke, and home dampness, the OR of 42.0 indicated a very high risk for allergic sensitization to cats, although CIs were broad (95 percent CI, 3.7–472.8). The investigators concluded that secondhand smoke exposure may promote atopic sensitization in children with asthma. The study did not control for in utero exposure to smoking (Lindfors et al. 1999).

A six-year prospective cohort study of 408 Danish children and adolescents aged 7 to 17 years initially included measurements of IgE and skin tests to common allergens. Only a single measurement of IgE was available when the study began. An analysis of individuals who were not atopic at the time of the first examination showed that exposure to secondhand tobacco smoke from maternal smoking increased the risk for a positive skin-prick test at the second evaluation (OR = 2.0 [95 percent CI, 1.3–3.1]), but changes in IgE levels could not be assessed. The authors concluded that exposure to secondhand smoke was associated with an increased risk of sensitization to common aeroallergens in adolescence (Ulrik and Backer 2000).

Other recent investigations have focused on children in the first three to four years of life, a critical time for alveolar and immune system development. In a birth cohort study, 981 children of the original cohort of 1,218 children were tested by skin prick for common aeroallergens at one, two, and four years of age (Tariq et al. 2000). An inverse association was noted for exposure to maternal smoking during pregnancy and childhood and the development of allergic sensitization at four years of age. Among children whose mothers smoked during pregnancy and/or after birth, 31.4 percent were not sensitized to aeroallergens versus 21.2 percent who were (p <0.05). Paternal smoking was not associated with allergen sensitization or skin-test reactivity (17.2 percent of those exposed versus 20.5 percent who were not exposed to paternal smoking). The investigators noted that secondhand smoke exposure from paternal sources may have been underestimated because more mothers than fathers were available for interviews (Tariq et al. 2000). Kulig and colleagues (1999) found that in children three years of age who had been exposed to secondhand smoke prenatally and postnatally, secondhand smoke exposure and sensitization to aeroallergens were not associated.

For the updated meta-analysis of the evidence relating parental smoking to allergic sensitization in children as measured by a skin-prick test (Strachan and Cook 1998b), 50 potentially relevant studies were identified, 3 of which yielded sufficient data to calculate the effect measure of interest. One of these papers was not included in the synthesis (Burr et al. 1997) because it measured allergic sensitization in neonates instead of in children. Two papers (Arshad et al. 1993; Tariq et al. 2000) analyzed the same data, and the more recent results (Tariq et al. 2000) are included here. In both the 1998 synthesis and this meta-analysis, the effect measure compared the relative odds of positive skin-prick reactions in exposed versus unexposed children. Studies were grouped according to the timing of secondhand smoke exposure: perinatal (maternal smoking during pregnancy and parental smoking from infancy to four years of age) and childhood (parental smoking at five or more years of age). The updated meta-analysis includes 10 papers (Table 6.22). There was significant heterogeneity among the studies. The heterogeneity does not seem to be explained by study characteristics such as design, location, age group, or exposure measure.

Table 6.22

Table 6.22

Studies relating parental smoking to skin-prick positivity in children

The results of studies of perinatal exposure were the least heterogeneous; the pooled ORs suggest a nonsignificant reduction in risk among children exposed to secondhand smoke (Table 6.23 and Figure 6.11). The evidence is less consistent for childhood exposures (Figure 6.12 and Table 6.23). The random effects estimate, which is more appropriate than the fixed effects given the significant heterogeneity, shows a small and nonsignificant increase in risk associated with exposure, although this conclusion is limited by the small number of studies included in this analysis.

Table 6.23

Table 6.23

Summary of pooled odds ratios (95% confidence intervals) in skin-prick positivity comparing unexposed children with children exposed to secondhand smoke at various time points

Figure 6.11. Odds ratios for the association between parental smoking during pregnancy and infancy and skin-prick positivity.

Figure 6.11

Odds ratios for the association between parental smoking during pregnancy and infancy and skin-prick positivity. Note: Size of boxes is proportional to the weight of each study in the pooled odds (more...)

Figure 6.12. Odds ratios for the association between parental smoking during childhood and skin-prick positivity.

Figure 6.12

Odds ratios for the association between parental smoking during childhood and skin-prick positivity. Note: Size of boxes is proportional to the weight of each study in the pooled odds ratio (OR). (more...)

Considering all of the studies together, the random effects estimate is 1.10 (95 percent CI, 0.85–1.42), a nonsignificant increase in risk among exposed children (Figure 6.13 and Table 6.23). The results of these studies confirm those of the previous meta-analysis: parental smoking during pregnancy or childhood is not consistently associated with an increased risk of allergic sensitization.

Figure 6.13. Odds ratios for the association between parental smoking and skin-prick positivity.

Figure 6.13

Odds ratios for the association between parental smoking and skin-prick positivity. Note: Size of boxes is proportional to the weight of each study in the pooled odds ratio (OR). Solid line represents (more...)

Atopic Disease

Findings from recent investigations of atopic disease indicators such as allergic symptoms, eczema, rhinitis, and dermatitis are generally consistent with the earlier systematic review. Studies document that secondhand smoke exposure affects cellular biomarkers. Vinke and colleagues (1999) demonstrated that IgE-positive cells and eosinophils were higher in the nasal mucous of children exposed to secondhand smoke than in unexposed children. The researchers concluded that although secondhand tobacco smoke exposure led to a tissue infiltrate in biopsy specimens that resembles that in the nasal mucosa of children with allergy, a key difference was the lack of IgE-positive mast cells in biopsy specimens from the non-atopic children exposed to secondhand smoke (Vinke et al. 1999).

In a prospective cohort study of 6,068 children born in 1970, a follow-up for indicators of atopy was carried out at 5, 10, and 16 years of age by questioning parents (Lewis and Britton 1998). Maternal smoking was measured as “maternal smoking during pregnancy” and “current maternal smoking.” The findings did not support the hypothesis that maternal smoking during pregnancy or current maternal smoking contributes to the development of atopy. In fact, the occurrence of hay fever at 16 years of age was less common in those with the highest levels smoked by the mother (current smoking OR = 0.78 [95 percent CI, 0.67–0.92]). A risk for eczema at 16 years of age was not associated with current maternal smoking.

Kalyoncu and colleagues (1999) conducted two questionnaire surveys five years apart to evaluate prevalence rates for asthma, allergic disease, and risk factors among primary school-age children. The second survey included 358 boys and 380 girls aged 6 through 13 years. In this sample, smoking at home was associated with the occurrence of allergic rhinitis (OR = 1.84 [95 percent CI, 1.3–3.0]), and the occurrence of allergic symptoms during the past 12 months was associated with secondhand tobacco smoke exposure (OR = 1.74 [95 percent CI, 1.18–2.56]) (Kalyoncu et al. 1999).

In a retrospective cohort study of 1,934 children, there was no significant association between maternal smoking and atopy (OR = 1.16 [95 percent CI, 0.95–1.43]), hay fever (OR = 1.04 [95 percent CI, 0.82–1.32]), or eczema (OR = 0.97 [95 percent CI, 0.75–1.26]) (Farooqi and Hopkin 1998). The authors concluded that genetic factors constitute the main risk for the development of atopy in children. With an OR of 1.97 (95 percent CI, 1.46–2.66), maternal atopy was a predictor of the development of atopy in these children (Farooqi and Hopkin 1998).

As part of ISAAC, parents answered a supplemental questionnaire regarding indoor environmental exposures and childhood symptoms of atopic rhinitis. For participants in Austria, there were questionnaire responses for 18,606 children aged six through nine years (Zacharasiewicz et al. 2000). Multiple indoor environmental exposures were considered in the analyses, including maternal smoking during pregnancy and/or while breastfeeding, secondhand smoke exposure, mattress and bedding type, home dampness, cooking fuels, home heating, and indoor pets. Overall, there was no difference between indoor environmental exposures in children with rhinitis symptoms only during the pollen season versus those with symptoms year round. Maternal smoking during pregnancy and after birth while the mother breastfed was associated with an increased risk for atopic rhinitis symptoms in the 12 months before the interview (OR = 1.28 [95 percent CI, 1.07–1.52]). There was also evidence of a dose-response relationship: nasal symptoms in the previous 12 months increased if household smokers smoked 50 or more cigarettes per day in the home (OR = 2.9 [95 percent CI, 1.21–6.95]) (Zacharasiewicz et al. 2000).

Heterogeneity in the measures of allergic sensitization across the studies limits comparisons. There are no prospective cohort studies that demonstrate longitudinal changes in IgE levels associated with prenatal and postnatal secondhand smoke exposure. Assessments of parental and sibling symptoms are critical to these studies, as those children predisposed to the development of allergic sensitization secondary to secondhand smoke exposure may be those most genetically predisposed to the development of atopy, and gene-environment interactions will need to be considered in future studies of secondhand smoke exposure in children.

Evidence Synthesis

There are multiple mechanisms by which secondhand smoke exposure might alter the risk for allergic diseases in infants and children. Exposure to tobacco smoke components from maternal smoking during pregnancy might have lasting effects on lung and systemic immunophenotypes. Exposures after birth might also affect immunophenotype or increase susceptibility to sensitization by common allergens.

The observational evidence across a range of outcome measures is inconsistent, however. The inconsistency may partially reflect the limited number of studies for any particular outcome and the methodologic complexities of studies on atopic disorders.

Conclusion

  1. The evidence is inadequate to infer the presence or absence of a causal relationship between parental smoking and the risk of immunoglobulin E-mediated allergy in their children.

Implications

Studies on secondhand smoke exposure and atopy need to be prospective in design and should track exposures back to the pregnancy. Further studies on secondhand smoke and atopy in childhood are needed, but the studies need to be large enough and need to have sufficient and valid measurements of allergic phenotype. Future studies also need to address potential genetic determinants of susceptibility, particularly as they modify the effect of secondhand smoke.

Lung Growth and Pulmonary Function

Beginning with the 1984 report (USDHHS 1984), the U.S. Surgeon General’s reports in this series have covered the adverse effects of exposure to secondhand smoke, including effects from maternal smoking during pregnancy and effects on lung growth from exposure during infancy and childhood. Both cross-sectional and cohort studies on this topic have used lung function level as the primary indicator (Table 6.24). The level of lung function achieved at any particular age and measured cross-sectionally is an indicator of the rate of growth of function up to that age; cohort studies with repeated measurements of lung function directly estimate the rate of growth. The 1986 Surgeon General’s report, The Health Consequences of Involuntary Smoking, reviewed 18 cross-sectional and cohort studies and concluded that “available data demonstrate that maternal smoking reduced lung function in young children” (USDHHS 1986, p. 54). The report further suggests that although this reduction is small, with an average of 1 to 5 percent, “some children might be affected to a greater extent, and even small differences might be important for children who become active cigarette smokers as adults” (USDHHS 1986, p. 54). The EPA issued its risk assessment in 1992 and concluded that the decline in lung function associated with exposure to secondhand smoke represented a causal effect (USEPA 1992). Similar conclusions were reached by the California Environmental Protection Agency (NCI 1999) and WHO (1999). Thus, for nearly two decades the weight of evidence has been sufficient to conclude that prenatal and postnatal tobacco smoke exposure is associated with a decrease in lung function in childhood. As discussed earlier in this chapter (see “Mechanisms of Health Effects from Secondhand Tobacco Smoke”), lung maturation and growth decrements secondary to exposure are reflected in changes in measured pulmonary function.

Table 6.24

Table 6.24

Cross-sectional and cohort studies that used lung function level as the primary indicator of adverse effects of exposure to secondhand smoke

A 1998 meta-analysis by Cook and colleagues (1998) concluded that maternal smoking was associated with reduced ventilatory function assessed by spirometry. In a quantitative synthesis of 21 cross-sectional studies, the effects of parental smoking on lung function were reductions of the FVC by 0.2 percent (95 percent CI, −0.4–0.1), the FEV1 by 0.9 percent (95 percent CI, −1.2 to −0.7), the MEFR by 4.8 percent (95 percent CI, −5.4 to −4.3), and the end-expiratory flow rate (EEFR) by 4.3 percent (95 percent CI, −5.3 to −3.3). The meta-analysis also considered six prospective cohort studies and found only a small effect of current exposure on decreased growth in lung function. The researchers attributed most of the decreased growth to a lasting consequence of in utero exposure from maternal smoking (Cook et al. 1998).

This discussion considers some of the studies included in this 1998 meta-analysis in addition to studies published subsequently. The studies are both cross-sectional and cohort in design, include data on maternal smoking during pregnancy and after birth, and indicate that maternal smoking during pregnancy has a substantially greater adverse effect. As discussed above, maternal smoking affects lung development in utero perhaps by a direct toxic effect, by gene regulation, or by leading to developmental abnormalities. The number of airways in the lung is considered fixed by the time a child is born, but the number of alveoli in the lung increases until four years of age (Dezateux and Stocks 1997). The period from gestation to four years of age thus represents a vulnerable time for lung growth and development, and exposures during this time are potentially the most critical for structural and functional lung development and performance. This section reviews the evidence that associates different phases of lung growth and development with corresponding ages.

Neonatal and Infant Lung Function and Growth

Evaluating lung function in neonates and infants is challenging because of an inability of the young child to cooperate with testing. However, methods that do not rely on cooperation from the child have been developed and standardized to assess pulmonary function during this period of ongoing lung development. The FRC is the most common measure of lung volumes performed in infants and is an indicator of normal lung volume growth. Measures of FRC can be completed using gas dilution (nitrogen washout) techniques or plethysmography, although plethysmographic measures are more dif cult to perform accurately with this age group. Airway resistance can be measured using plethysmography; lung resistance and compliance can be measured using esophageal manometry and forced oscillation methods. The partial forced expiratory maneuver can be used to obtain estimates of the forced expiratory flow rate (FEFR). This maneuver is performed using an inflatable jacket around the thorax of the infant, who is sedated and in the supine position. A rapid mechanical squeeze of the thorax by the jacket accomplishes the expiratory maneuver. With exhalation data from the FRC, partial expiratory flow maneuvers can be normalized and provide information on lung growth and disease in infants. These methods have been used both clinically and in research. The relationship of these infant lung function tests to standard spirometry, which can be measured reproducibly from around five years of age, is still unclear; researchers have published reviews of infant lung function measurements (Stocks et al. 2001; Davis 2003).

Hanrahan and colleagues (1992) conducted a birth cohort study in east Boston that was designed to measure the effect of maternal smoking during and after pregnancy on infant lung function after birth. Maternal reports of smoking during pregnancy were validated against measures of urinary cotinine. In 80 infants studied at a mean age of 4.2 (±1.9) weeks of age, there was a reduced flow in the FRC among infants born to mothers who had smoked during pregnancy (74.3 milliliters [mL] per second) compared with infants whose mothers had not smoked during pregnancy (150.4 mL per second, p = 0.0007). The effects were independent of effects from secondhand smoke on gestational age and birth weight. After stratification by prenatal exposure, the flow rates were not associated with postnatal exposure.

Tager and colleagues (1995) investigated the growth of pulmonary function in 159 infants in the same east Boston cohort. Infant pulmonary function tests were evaluated at 2 to 6 weeks, 4 to 6 months, 9 to 12 months, and 18 months of age using partial expiratory flow volume curves and helium dilution measures for the FVC to evaluate the effects of prenatal tobacco smoke exposure on lung function growth in the first 18 months of life. Maternal smoking during pregnancy was associated with a decrease in the FRC itself (9.4 ± 4.3 mL, p = 0.03) and a decrease in the FRC flow rate (33 ± 12.3 mL per second, p = 0.0008); these estimates were adjusted for the growth of the child. Because of the longitudinal structure of the data, including lung function assessment shortly after birth, the study data could separate the effects of prenatal and postnatal exposure. The study demonstrated an effect of maternal smoking on the FEFR at the FRC, with a multivariate analysis showing that the effect was secondary to prenatal but not to postnatal exposure.

An Australian cohort study that recruited participants from a prenatal care clinic assessed secondhand smoke exposure from a questionnaire and evaluated cotinine levels. The researchers tested lung function in 461 infants by measuring the TPTEF:TE. Measurements at one to six and one-half days of age showed lower values in infants whose mothers smoked more than one-half pack of cigarettes per day (Stick et al. 1996).

Two studies published since the 1998 meta-analysis (Cook et al. 1998) also assessed the effects of maternal smoking during pregnancy on infants (Hoo et al. 1998; Dezateux et al. 1999). Hoo and colleagues (1998) measured the VmaxFRC and TPTEF:TE in a cohort of preterm infants born at a mean gestational age of 33.5 weeks. Of the 108 infants in the cohort, 40 were born to mothers who had smoked during pregnancy. The TPTEF:TE was lower in infants exposed to second-hand smoke in utero (mean 0.369, SD 0.109) compared with unexposed infants (mean 0.426, SD 0.135, p ≤ 0.024). This was the first study to evaluate preterm infants, and the investigators found an effect of maternal smoking on lung development by the 33rd week of gestation.

A study by Dezateux and colleagues (1999) investigated the association of postnatal maternal smoking with measures of Specific airway conductance at eight weeks and at one year of age. The initial cohort consisted of 108 term infants with a lung function assessment at eight weeks of age; 100 were available for a longitudinal follow-up at one year of age. Specific air-way conductance at end expiration (sGawEE) was used as a measure of airway function with a correction for airway size. In multivariate models that included physician-diagnosed wheeze, a family history of measured at eight weeks, and a asthma, sGawEE maternal history of postnatal smoking, there was a decrease of 0.40 seconds per kilopascal (unit of pressure) (95 percent CI, −0.71 to −0.10, p = 0.01) in sGaw among infants of mothers who had smoked in the early postnatal period. The authors concluded that early postnatal maternal smoking was an important cause of altered airway function in the infant, with implications for lung growth and development.

Childhood Lung Function and Growth

Researchers have conducted multiple studies of older children to characterize the effects of secondhand smoke exposure on lung growth and development beyond the neonate or infancy stage. Some of these studies evaluated in utero, postnatal, and current tobacco smoke exposures. Although several large, cross-sectional studies (presented below) have been published since the 1998 meta-analysis (Cook et al. 1998), there has been little additional longitudinal evidence since 1997.

One cross-sectional study was carried out in 24 U.S. and Canadian cities to assess the effects of air pollution on child respiratory health. Using data from 8,863 children aged 8 to 12 years in 22 of the cities, Cunningham and colleagues (1994) found that lung function was lower in children whose mothers had smoked during pregnancy. The study recorded maternal smoking histories and pulmonary function measures. Regardless of whether these mothers were still smoking the year before study assessment, their children had lower spirometric measures than children with no in utero or postnatal exposure to maternal smoking. In comparisons of exposed and unexposed children, adjusted findings in exposed children included a 5.7 percent reduction (95 percent CI, −7.7 to −3.6 percent) in the FEF that was between 65 and 75 percent of the FVC, a 4.9 percent reduction (95 percent CI, −6.5 to −3.2 percent) in the FEF measured between 25 and 75 percent of the FVC (FEF25–75), and a 1.7 percent reduction (95 percent CI, −2.4 to −1.0 percent) in the measure of the FEV during the first three-fourths of a second of exhalation (FEV0.75). Current maternal smoking was not associated with spirometric decrements. There were 75 children whose mothers had smoked only during the prepartum but not in the postpartum phase. These children had FEF25–75 values that were 11 percent lower (95 percent CI, −16.5 to −5.1, p = 0.0004) than those in children of mothers who had never smoked. In this cohort, 6,508 mothers had not smoked during pregnancy. Multivariate models that adjusted for gender, height, age, parental education, place of residence, and current tobacco smoke exposure in the home (maternal, paternal, or other smokers in the home) documented an estimated 2.8 percent decrease (p = 0.026) in the FEF25–75 for postpartum maternal smoking up to two years of age of the child. This estimate is about half the size of the effect of smoking during pregnancy. The authors concluded that the decrements in lung function associated with maternal smoking during pregnancy were not explained by current maternal smoking; the observation that these effects were most significant on flow measures suggests involvement, likely inflammation and obstruction, of the small airways.

Several additional cross-sectional studies have been reported since Cunningham and colleagues (1994) conducted their large, cross-sectional analysis. Gilliland and colleagues (2000) investigated 3,357 children in 12 southern California communities and assessed the effects of maternal prenatal and postnatal smoking on pulmonary function measures in children. Current and past secondhand smoke exposures and in utero maternal smoking were assessed from a questionnaire that was completed by parents of fourth-, seventh-, and tenth-grade students. In utero exposure was associated with reduced flow rates measured by spirometry, but not with reductions in the FEV1. More Specifically, the peak expiratory flow rate was reduced by 3 percent (95 percent CI, −4.4 to −1.4 percent), the mean MEF (closely equivalent to the FEF25–75) was reduced by 4.6 percent (95 percent CI, −7.0 to −2.3 percent), and the FEF at 75 percent of vital capacity (FEF75) was reduced by 6.2 percent (95 percent CI, −9.1 to −3.1 percent). Adjustment for confounding factors such as secondhand smoke from the mother, father, or other adult household smokers; gender; race; school grade; income; personal smoking; or parental education levels did not significantly alter the effect estimate for in utero exposure. The researchers concluded that in utero exposure to maternal secondhand smoke was independently associated with a reduction in lung function among school-age children. The authors also suggested that the predominant reduction in flows may reflect an effect of in utero exposure on distal airway maturation and growth during in utero development.

The Children’s Health Study evaluated the effects of in utero and postnatal secondhand smoke exposure on lung function in boys and girls with and without a history of asthma. In utero exposure from maternal smoking and secondhand smoke exposure postnatally (from maternal, paternal, or other adult household members) was associated with a measured decrease in lung function in 5,263 children (Li et al. 2000). Children exposed to tobacco smoke in utero from maternal smoking had reductions in maximal MEF and FEV1/FVC ratios. Specifically, the maximal MEF decreased by 5.9 percent (95 percent CI,−8.4 to −3.4 percent, p <0.001) in boys and by 3.9 percent (95 percent CI, −6.3 to −1.5 percent) in girls (4.2 and 3.0 percent, respectively, when children with asthma were excluded). The FEV1/FVC ratio decreased by 2.0 percent (95 percent CI, −2.7 to −1.2 percent, p <0.001) in boys and by 1.7 percent (95 percent CI, −2.3 to−1.0 percent) in girls (1.6 and 1.2 percent, respectively, when children with asthma were excluded). In this study, decreased air flow in children without asthma was significantly associated with current secondhand smoke exposure from two or more current smokers.

The NHANES III included a cross-sectional U.S. national sample of 5,400 children aged 4 through 16 years (Mannino et al. 2001). The study data included a respiratory symptoms questionnaire, spirometric measurements, and serum cotinine levels. Participants were stratified by cotinine levels to assess the effects of secondhand tobacco smoke exposure on a variety of health outcomes including lung function. Prenatal secondhand smoke exposure was also retrospectively assessed in the group of children aged 4 to 11 years. Children in the highest cotinine tertile were more likely to have a FEV1/FVC ratio of less than 0.8 (OR = 1.8 [95 percent CI, 1.3–2.4]). Children exposed to secondhand smoke had reductions in the FEV1 (−1.8 percent [95 percent CI, −3.2 to −0.4 percent]), the FEV1/FVC ratio (−1.5 percent [95 percent CI, −2.2 to −0.8 percent]), and the maximal MEF (−5.9 percent [95 percent CI, −8.1 to −3.4 percent]).

Lung Function

To date, prospective cohort studies have not incorporated measurements of lung function along with serial cotinine level measurements. On the other hand, reports of smoking by key household members have high validity and are likely to provide an adequate index of usual exposure to secondhand smoke. One small, prospective cohort study that assessed the effects of tobacco smoke on lung growth in adolescents used urine cotinine levels as a biomarker for active and secondhand tobacco smoke exposure (Bono et al. 1998). Questionnaires, urinary cotinine levels, and spirometric measurements were used to evaluate 394 schoolchildren aged 14 through 16 years. Approximately one year later, data from 333 adolescents were reassessed in multiple regression analyses. The reassessments revealed a trend for reductions in lung growth suggested by spirometry (FEV1), in association with active and involuntary smoking measured by serum cotinine levels. The effect on FEV1 growth, although small, demonstrated a dose-related linear trend (Bono et al. 1998).

In a meta-analysis of the cross-sectional evidence relating parental smoking to spirometric indices in children (Cook et al. 1998), new cross-sectional studies (published from 1997 to 2000) were identified by using the same search strategy that the 1998 review had used (Cook et al. 1998). Six additional studies were identified (Behera et al. 1998; Demissie et al. 1998; Bek et al. 1999; Gilliland et al. 2000; O’Connor et al. 2000; Mannino et al. 2001). Three of these studies (Behera et al. 1998; Bek et al. 1999; O’Connor et al. 2000) could not be included in this quantitative synthesis because they did not provide sufficient data to calculate the effect measure of interest (average percentage difference in spirometric index between exposed and unexposed children). The other three papers (Demissie et al. 1998; Gilliland et al. 2000; Mannino et al. 2001) were included in the following updated meta-analysis. One additional paper published before the 1998 synthesis (Rona and Chinn 1993) that was included in the present analysis had not been included in the 1998 quantitative synthesis—the data needed to calculate the effect measure of interest were not available at the time; the data have since become available. The data in this study were presented separately for girls and boys, and a combined estimate was obtained with a random effects method (Egger et al. 2001).

This analysis used the same effect measure that was used in the 1998 synthesis: the average difference in spirometric index between the exposed and unexposed children expressed as a percentage of the level in the unexposed group. Four different spirometric indices were considered: FVC, FEV1, MEFR, and EEFR. Pooled estimates of the percentage differences were calculated using both fixed and random effects models (Egger et al. 2001).

To determine whether the classification of exposure influenced the relationship between parental smoking and lung function, studies were pooled within exposure groups: both parents did versus did not smoke, mother did versus did not smoke, either parent did versus did not smoke, the highest cotinine category versus the lowest, and high levels of household secondhand tobacco smoke versus none. To test whether adjusting for variables other than age, gender, and body size affected the relationship, studies were pooled separately depending on what adjustments were made for other variables. A final assessment was then made as to whether adjustments for SES measures, such as parental education and social class, were assessed for possible effects on the pooled results.

Of the 26 studies included in the updated quantitative synthesis, 4 were not in the 1998 analysis. There was significant variability among studies for all spirometric measures except the EEFR (Figures 6.146.17 and Table 6.25). Heterogeneity was to be expected given the variability in secondhand smoke exposure classifications. Pooling all of the studies found statistically significant reductions in three out of the four measures of lung function (FEV1, MEFR, and EEFR) for children exposed to secondhand smoke in their homes compared with unexposed children. The pooled percentage differences in lung function were smallest for FVC (−0.3 percent) and FEV1 (−1.2 percent) and larger for MEFR (−4.8 percent) and EEFR (−4.3 percent). The MEFR and EEFR are more sensitive indicators of airways function compared with the FVC and the FEV1.

Figure 6.14. Percentage difference in the forced vital capacity (FVC) between children of smokers and children of nonsmokers in studies included in the meta-analysis.

Figure 6.14

Percentage difference in the forced vital capacity (FVC) between children of smokers and children of nonsmokers in studies included in the meta-analysis. *Pooled difference is from the fixed effects (more...)

Figure 6.17. Percentage difference in the end-expiratory flow rate (EEFR) between children of smokers and children of nonsmokers in studies included in the meta-analysis.

Figure 6.17

Percentage difference in the end-expiratory flow rate (EEFR) between children of smokers and children of nonsmokers in studies included in the meta-analysis. *Pooled difference is from the fixed (more...)

Table 6.25

Table 6.25

Summary of pooled percentage differences in cross-sectional studies of lung function in children exposed to secondhand smoke compared with unexposed children

Figure 6.15. Percentage difference in the forced expiratory volume in 1 second (FEV1) between children of smokers and children of nonsmokers in studies included in the meta-analysis.

Figure 6.15Percentage difference in the forced expiratory volume in 1 second (FEV1) between children of smokers and children of nonsmokers in studies included in the meta-analysis

*Pooled difference is from the fixed effects meta-analysis.

Pooled difference is from the random effects meta-analysis.

Figure 6.16. Percentage difference in the mid-expiratory flow rate (MEFR) between children of smokers and children of nonsmokers in studies included in the meta-analysis.

Figure 6.16Percentage difference in the mid-expiratory flow rate (MEFR) between children of smokers and children of nonsmokers in studies included in the meta-analysis

*Pooled difference is from the fixed effects meta-analysis.

Pooled difference is from the random effects meta-analysis.

The association between exposure to secondhand smoke and lung function differed according to the exposure classification, but not in a consistent pattern across the four lung function measures (Table 6.26). Adjusting for factors in addition to age, gender, and body size did not significantly affect the associations between secondhand smoke exposure and lung function (Table 6.27). Adjusting for social class had little effect on the FVC, FEV1, and MEFR measures, but nearly doubled the percentage difference in the EEFR (Table 6.27).

Table 6.26

Table 6.26

Pooled percentage differences in lung function according to secondhand smoke exposure category (random effects results)

Table 6.27

Table 6.27

Pooled percentage differences in lung function according to confounders adjusted for (random effects results)

The evidence of associations between secondhand smoke exposure and lung function growth and development continues to come largely from cross-sectional studies. The resulting data indicate the level of lung function at only a single age, which at that point is considered indicative of the cumulative consequences of the various factors influencing lung function growth, including prenatal and postnatal maternal smoking. Prospective cohort studies have the advantages of directly measuring lung function over time and directly estimating the rate of change, but few have been carried out because of cost and logistical constraints.

Evidence Synthesis

Smoking during pregnancy exposes the developing lung to a variety of toxins and reduces the delivery of oxygen to the fetus (USDHHS 2001). Animal models indicate structural consequences that may underlie the physiologic effects that are well documented shortly after birth. Secondhand smoke exposure from parents who smoke would be expected to lead to pulmonary inflammation that would be sustained across childhood.

Thus, there is substantial biologic plausibility for causation of reduced lung growth by secondhand smoke exposure. Multiple studies have measured lung function shortly after birth and document the adverse effects on lung function from maternal smoking during pregnancy. The pattern of abnormalities is suggestive of a persistent adverse effect on the airways of the fetus from maternal smoking during pregnancy.

There is also substantial evidence from both cross-sectional and cohort studies of a sustained effect from in utero exposure, as well as an additional adverse effect from postnatal exposure. Multiple studies have shown cumulative consequences of both prenatal and postnatal exposures. Across the set of studies, potentially important confounding factors have been given consideration and the adverse effects of secondhand smoke exposure on lung function cannot be attributed to other factors.

In the context of this body of evidence against causal criteria, the effects of prenatal and postnatal exposures merit separate consideration because they correspond to substantially different phases of development and potential susceptibility. For both exposures, the evidence is substantial and consistent. There are multiple bases for biologic plausibility, and the temporal relationships of exposures with the outcome measures are appropriate.

Conclusions

  1. The evidence is sufficient to infer a causal relationship between maternal smoking during pregnancy and persistent adverse effects on lung function across childhood.
  2. The evidence is sufficient to infer a causal relationship between exposure to secondhand smoke after birth and a lower level of lung function during childhood.

Implications

Lung growth continues throughout childhood and adolescence and is completed by young adulthood, when lung growth peaks and then begins to decline as a result of aging, smoking, and other environmental factors. The evidence shows that parental smoking reduces the maximum achieved level, although not to a degree (on average) that would impair individuals. Nonetheless, a reduced peak level increases the risk for future chronic lung disease, and there is heterogeneity of the effect so that some exposed children may have a much greater reduction than the mean. In addition, children of smokers are more likely to become smokers and thus face a future risk for impairment from active smoking.

Conclusions

Lower Respiratory Illnesses in Infancy and Early Childhood

  • 1. The evidence is sufficient to infer a causal relationship between secondhand smoke exposure from parental smoking and lower respiratory illnesses in infants and children.
  • 2. The increased risk for lower respiratory illnesses is greatest from smoking by the mother.

Middle Ear Disease and Adenotonsillectomy

  • 3. The evidence is sufficient to infer a causal relationship between parental smoking and middle ear disease in children, including acute and recurrent otitis media and chronic middle ear effusion.
  • 4. The evidence is suggestive but not sufficient to infer a causal relationship between parental smoking and the natural history of middle ear effusion.
  • 5. The evidence is inadequate to infer the presence or absence of a causal relationship between parental smoking and an increase in the risk of adenoidectomy or tonsillectomy among children.

Respiratory Symptoms and Prevalent Asthma in School-Age Children

  • 6. The evidence is sufficient to infer a causal relationship between parental smoking and cough, phlegm, wheeze, and breathlessness among children of school age.
  • 7. The evidence is sufficient to infer a causal relationship between parental smoking and ever having asthma among children of school age.

Childhood Asthma Onset

  • 8. The evidence is sufficient to infer a causal relationship between secondhand smoke exposure from parental smoking and the onset of wheeze illnesses in early childhood.
  • 9. The evidence is suggestive but not sufficient to infer a causal relationship between secondhand smoke exposure from parental smoking and the onset of childhood asthma.

Atopy

  • 10. The evidence is inadequate to infer the presence or absence of a causal relationship between parental smoking and the risk of immunoglobulin E-mediated allergy in their children.

Lung Growth and Pulmonary Function

  • 11. The evidence is sufficient to infer a causal relationship between maternal smoking during pregnancy and persistent adverse effects on lung function across childhood.
  • 12. The evidence is sufficient to infer a causal relationship between exposure to secondhand smoke after birth and a lower level of lung function during childhood.

Overall Implications

The extensive evidence considered in this chapter causally links parental smoking to adverse health effects in children. The association between parental smoking and childhood respiratory disease is stronger at younger ages, a pattern plausibly explained by a higher level of exposure to secondhand smoke among infants and preschool-age children for any given level of parental smoking. In general, associations with maternal smoking are stronger than with paternal smoking, but for several outcomes, associations were found for smoking by the father in homes where the mother does not smoke. This finding argues strongly for an independent adverse effect of a post-natal involuntary (environmental) exposure to secondhand smoke in the home. There may be an additional hazard related to prenatal exposure of the fetus to maternal smoking during pregnancy (USDHHS 2001, 2004). The published evidence does not adequately separate the independent effects on childhood respiratory health of prenatal versus postnatal exposure to maternal smoking. This unresolved research issue should not detract from the public health message that smoking by either parent is potentially damaging to the health of children.

Interpretation of the evidence is perhaps most complex in relation to childhood asthma, which is a term generally applied to a mixed group of clinical phenotypes. Recurrent wheeze illnesses are common among young children, and there is controversy about whether these illnesses should all be classified as “asthma.” Cohort studies show that symptoms do not persist for many children beyond the first few years of life. The balance of evidence strongly supports a causal relationship between parental smoking and the incidence of wheeze illnesses in infancy, the prevalence of wheeze and related symptoms among schoolchildren, and the relative severity of disease among children with physician-diagnosed asthma. These are all important indicators of a substantial and potentially preventable public health burden.

The evidence related to the wheeze illnesses can be separated to an extent from that related to a clearer clinical phenotype of asthma, a chronic condition of variable air flow obstruction with a heightened susceptibility to environmental triggers of bronchospasm. The evidence is less clear as to whether parental smoking initiates the disease among previously healthy children. Because the clinical diagnosis of asthma relies to a large extent upon a history of recurrent wheeze attacks or other chest illnesses, any exposure (including parental smoking) that increases the incidence of such episodes will tend to be associated with an apparent increase in the incidence of diagnosed “asthma,” even if secondhand smoke exposure does not contribute to the incidence directly. Studies of nonspecific bronchial responsiveness, a surrogate for the asthma phenotype, offer some insights into the long-term susceptibility that underlies chronic asthma. Secondhand smoke exposure is linked to an increase in responsiveness, beginning with in utero exposure. However, bronchial responsiveness is also nonspecifically and transiently increased following respiratory tract infections. For this reason, the conclusion regarding parental smoking as a cause of childhood asthma has been phrased in less definite terms than the conclusions relating to asthma prevalence and severity.

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